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INTERFERON GAMMA
LATEST LITERATURE
1: Journal of neural transmission (Vienna, Austria : 1996), 2010 Sep 2, 34(7)
Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders.
[Abstract]This review of literature and our data suggests that up-regulated production of interferon-gamma (IFNG) in periphery and brain triggers a merger of tryptophan (TRY)-kynurenine (KYN) and guanine-tetrahydrobiopterin (BH4) metabolic pathways into inflammation cascade involved in aging and aging-associated medical and psychiatric disorders (AAMPD) (metabolic syndrome, depression, vascular cognitive impairment). IFNG-inducible KYN/pteridines inflammation cascade is characterized by up-regulation of nitric oxide synthase (NOS) activity (induced by KYN) and decreased formation of NOS cofactor, BH4, that results in uncoupling of NOS that shifting arginine from NO to superoxide anion production. Superoxide anion and free radicals among KYN derivatives trigger phospholipase A2-arachidonic acid cascade associated with AAMPD. IFNG-induced up-regulation of indoleamine 2,3-dioxygenase (IDO), rate-limiting enzyme of TRY-KYN pathway, decreases TRY conversion into serotonin (substrate of antidepressant effect) and increases production of KYN associated with diabetes [xanthurenic acid (XA)], anxiety (KYN), psychoses and cognitive impairment (kynurenic acid). IFNG-inducible KYN/pteridines inflammation cascade is impacted by IFNG (+874) T/A genotypes, encoding cytokine production. In addition to literature data on KYN/TRY ratio (IDO activity index), we observe neopterin levels (index of activity of rate-limiting enzyme of guanine-BH4 pathway) to be higher in carriers of high (T) than of low (A) producers alleles; and to correlate with AAMPD markers (e.g., insulin resistance, body mass index, mortality risk), and with IFN-alpha-induced depression in hepatitis C patients. IFNG-inducible cascade is influenced by environmental factors (e.g., vitamin B6 deficiency increases XA formation) and by pharmacological agents; and might offer new approaches for anti-aging and anti-AAMPD interventions.
2: Cleveland Clinic journal of medicine, 2010 Sep, 77(9)
Interferon-gamma-release assays: Better than tuberculin skin testing?
[Abstract]Although the tuberculin skin test has long been the standard for detecting latent tuberculosis infection, it has many limitations. Interferon-gamma-release assays are gaining acceptance as an alternative. In this paper we present cases to illustrate how these new tests can be used and how to interpret the results.
3: Transplant infectious disease : an official journal of the Transplantation Society, 2010 Aug 29, 42(9)
Splenic autotransplantation reverses interferon-gamma and nitric oxide production and resistance to Listeria monocytogenes in splenectomized mice.
[Abstract]S.M. Perobelli, C.C.S. Alves, A.B. Rezende, R.E. Farias, S.I. Nunes, H.C. Teixeira. Splenic autotransplantation reverses interferon-gamma and nitric oxide production and resistance to Listeria monocytogenes in splenectomized mice. Transpl Infect Dis 2010. All rights reserved Abstract: Splenectomized mice control Listeria monocytogenes infection better than non-splenectomized mice. Here, BALB/c mice subjected to splenectomy and autogenous grafting of spleen were evaluated after 3 and 7 days of intravenous L. monocytogenes infection. The group of splenectomized animals (SP) presented a lower number of bacteria in the liver in comparison with both the sham-operated control group (CT) and the group that received splenic autotransplantation (AT) in the retroperitoneal site. The AT group presented bacterial counts in the liver similar to the CT group. SP animals showed larger production of interferon-gamma (IFN-gamma) and nitric oxide (NO) in the liver in comparison with CT and AT, this being associated with greater accumulation of mononuclear cells. IFN-gamma production by spleen cells after stimulation with heat-killed Listeria was similar between the AT and CT groups, suggesting that the implanted fragments behaved like the original organ. The autogenous grafting of spleen fragments reverses the resistance to L. monocytogenes infection found in splenectomized mice, associated with a reduced IFN-gamma and NO production in the liver. The present study shows that splenic autotransplantation restores the function of the spleen in splenectomized mice, even though in this case it does favor the susceptibility to L. monocytogenes infection.
4: Clinical rheumatology, 2010 Aug 25, 42(9)
A comparison of an interferon-gamma release assay and tuberculin skin test in refractory inflammatory disease patients screened for latent tuberculosis prior to the initiation of a first tumor necrosis factor alpha inhibitor.
[Abstract]Treatment with TNFalpha inhibitors increases risk of reactivating a latent tuberculosis\infection (LTBI). Therefore screening, prior to therapy with TNFalpha inhibitors, has been recommended, even in low-endemic areas such as well-developed Western Europe countries. We evaluated interferon-gamma release assay (IGRA), as opposed to tuberculin skin test (TST), for detection of LTBI in refractory inflammatory disease patients prior to the initiation of a first TNFalpha inhibitor. In addition, we evaluated the impact of impaired cellular immunity on IGRA. Patients starting on TNFalpha inhibition were screened for LTBI by TST and IGRA (Quantiferon-TB Gold). Data on tuberculosis exposure and Bacillus Calmette-Gu¨¦rin (BCG) vaccination were obtained. Cellular immunity was assessed by CD4(+) T lymphocyte cell count. Nine out of 56 patients (16.1%) tested positive for LTBI. A concordant positive result was present in three patients with a medical history of tuberculosis exposure. Six patients with discordant test results had either: (1) a negative TST and positive IGRA in combination with a medical history of tuberculosis exposure (n = 1) or (2) a positive TST and negative IGRA in combination with BCG vaccination (n = 3) or a medical history of tuberculosis exposure (n = 2). CD4(+) T lymphocyte cell counts were within normal limits, and no indeterminate results of IGRA were present. IGRA appears reliable for confirming TST and excluding a false positive TST (due to prior BCG vaccination) in this Dutch serie of patients. In addition, IGRA may detect one additional case of LTBI out of 56 patients that would otherwise be missed using solely TST. Immune suppression appears not to result significantly in lower CD4(+) T lymphocyte cell counts and indeterminate results of IGRA, despite systemic corticosteroid treatment in half of the patients. Confirmation in larger studies, including assessment of cost-effectiveness, is required.
5: Inflammatory bowel diseases, 2010 Aug 18, 8(2)
Factors impacting the results of interferon-gamma release assay and tuberculin skin test in routine screening for latent tuberculosis in patients with inflammatory bowel diseases.
[Abstract]BACKGROUND:: Screening for latent tuberculosis (LTB) including chest x-ray, tuberculin skin test (TST), and facultative whole blood interferon-gamma assay (IGRA) is part of routine management in inflammatory bowel disease (IBD) patients before starting therapy with tumor necrosis factor (TNF)-alpha inhibitors. However, in patients with immunomodulators (IM) TST and IGRA might show limitations. METHODS:: We aimed to evaluate the results from an IGRA (QuantiFERON-TB Gold in Tube) and TST as well as their concordance in 208 consecutive IBD patients with indications for anti-TNF-alpha therapy. Associations of both tests with risk factors for LTB were determined by logistic regression. RESULTS:: During screening, 149 patients (71.6%) were under IM therapy. In 26 (12.5%) patients TST was positive, whereas 15 (7.2%) patients showed a positive result from IGRA. IGRA failed on samples from 16/208 (7.7%) patients, resulting in 192/208 (92.3%) patients in whom results from both screening tests were available. Correlation between IGRA and TST results was fair (84.9%, kappa = 0.21). The presence of risk factors for LTB showed association with positive results of TST (odds ratio [OR] 3.7, 1.5-9.6) and IGRA (OR 3.5, 1.2-11.3). TST was associated furthermore with age (OR 1.06, 1.02-1.10) and signs indicative of LTB in chest x-ray (OR 4.9, 1.1-19.9). The IGRA was negatively influenced by IM therapy (OR 0.3, 0.1-0.9). CONCLUSION:: Our study reveals that results of IGRA are negatively affected by IM therapy. Thus, current guidelines for TB screening prior anti-TNF-alpha therapy appear inaccurate in patients under IM. Therefore, LTB screening might be best performed prior to initiation of IM treatment. (Inflamm Bowel Dis 2010;).
6: International archives of occupational and environmental health, 2010 Aug 19, 8(2)
Serial testing with the interferon-gamma release assay in Portuguese healthcare workers.
[Abstract]OBJECTIVES: Evidence for the utility of the new Mycobacterium tuberculosis (MTB) specific IFN-gamma release assays in diagnosing latent tuberculosis infection (LTBI) is growing. However, data concerning conversion and reversion rates in serial testing of healthcare workers (HCWs) with an interferon-gamma release assay are sparse. METHODS: Between February 2007 and September 2009, 670 HCWs in the University Hospital of Porto, Portugal were tested at least twice with QuantiFERON-TB((R)) Gold In-Tube (QFT) for LTBI. The tuberculin skin test (TST) was performed simultaneously. QFT was considered positive if INF-gamma >/=0.35 IU/mL. TST conversion was defined as an increase >/=10 or >/=6 mm compared to a baseline TST <10 mm. RESULTS: The second QFT was positive in 4.8% of the 376 HCWs with an INF-gamma concentration at baseline below 0.1 IU/mL but in 48.8% of the 41 HCWs with an INF-gamma concentration of 0.2 to <0.35 IU/mL. Out of 74 HCWs with a baseline INF-gamma concentration >/=3.0 IU/mL, 4 (5.4%) reversed while 27 out of 55 HCWs (49%) with a baseline INF-gamma concentration >/=0.35 to <0.7 IU/mL reversed to a negative QFT. Those 61 HCWs with TST conversion (increase >/=10 mm) were most often (78.7%) negative in both consecutive QFTs. CONCLUSION: Our data suggests the use of an uncertainty zone between 0.2 and 0.7 IU/mL in serial testing with QFT. As long as the knowledge regarding disease progression in QFT-positive persons is limited, persons pertaining to this zone should be retested before being offered preventive chemotherapy.
7: The Pediatric infectious disease journal, 2010 Sep, 29(9)
A presumed tubercular choroiditis based on interferon-gamma release assay and response to therapy.
[Abstract]Indoleamine 2,3-dioxygenase (IDO) is an enzyme that suppresses adaptive T-cell immunity by catabolizing tryptophan from the cellular microenvironment. Inhibition of IDO pathway might enhance the efficacy of immunotherapeutic strategies for cancer. We synthesized 1-alkyl-tryptophan targeted IDO inhibitors and compared their effects on IDO expression and activity in dendritic cells (DCs) with the common IDO inhibitor 1-methyl-DL: -tryptophan (1-MT). The IDO gene expression was examined by RT-PCR and realtime PCR. The toxicity of these analogs on the proliferation of DCs was detected by MTT assay. All of these analogs inhibited IDO expression and activity induced by IFN-gamma and showed no cytotoxicity to DCs at 100 muM. 1-MT intensively suppressed IDO1 expression and activity in DCs, and 1-propyl-tryptophan (1-PT) and 1-isopropyl-tryptophan (1-isoPT) moderately inhibited them. 1-Butyl-tryptophan (1-BT) and 1-ethyl-tryptophan (1-ET) mainly inhibited IDO2 expression. Our results suggest that those analogs differed in their inhibitory activity on IDO expression may give us a clue for developing active IDO inhibitors.
8: The Journal of pharmacology and experimental therapeutics, 2010 Aug 18, 8(2)
Modulation of Hepatic Cytochrome P450s by Citrobacter rodentium Infection in Interleukin-6- and Interferon-{gamma}-null Mice.
[Abstract]Following infection with Citrobacter rodentium, murine hepatic cytochrome P450 (P450) mRNAs are selectively regulated. Several serum pro-inflammatory cytokines are elevated, the most abundant being interleukin-6 (IL6). To elucidate the roles of cytokines in the regulation of P450s during infection, we orally infected wildtype , IL6-/-, or interferon-gamma-/- (IFNgamma-/-) female C57BL/6J mice with C. rodentium and analyzed hepatic P450 expression 7 days later. The majority of P450 mRNAs were equally affected by infection in each genotype, indicating that IL6 and IFNgamma are not the primary mediators of P450 down-regulation in this disease model. The down-regulation of CYP3A11 and 3A13 and induction of CYP2D9 mRNAs were attenuated in the IL6-/- mice, suggesting a role of IL-6 in the regulation of these P450s only. Similar evidence implicated IFNgamma in the regulation of CYP2D9, 2D22, 3A11, 3A25 and 4F18 mRNAs in C. rodentium infection, as well as CYP2B9, 2D22, 2E1 in the bacterial lipopolysaccharide (LPS) model of inflammation. This is the first indication of an in vivo role for IFNgamma in hepatic P450 regulation in disease states. The deficiency of IL6 or IFNgamma affected serum levels of the other cytokines. Moreover, experiments in cultured hepatocytes demonstrated that tumor necrosis factor-alpha (TNFalpha) is the most potent and efficacious of the cytokines tested in the regulation of murine P450 expression. It is therefore possible that part of the IFNgamma-/- and IL6-/- phenotypes could be attributed to the reduced levels of TNFalpha and part of the IFNgamma-/- phenotype could be due to reduced levels of IL6.
9: Research in veterinary science, 2010 Aug 16, 8(2)
IFN-g response to vaccination against tuberculosis in dairy heifers under commercial settings.
[Abstract]The purpose was to determine IFN-g release as a response to vaccination against tuberculosis in dairy heifers under commercial settings. Four-hundred pregnant heifers from ten herds were randomly allocated into four groups: (1) unvaccinated, (2) BCG vaccinated, (3) BCG vaccinated plus a CFPP400mug+polygen boost, and (4) BCG vaccinated plus a CFP200mug+polygen boost, under a completely randomized blocks design. A dose of 106CFU of BCG was delivered SC in the neck, then blood samples were taken at days 0, 30, 120, 210, 300 and 720 to estimate IFN-g release in response to bovine-PPD antigen. No significant difference (P>0.05) was observed in IFN-g release between groups at days 0 and 120. At days 30 and 210, vaccinated groups show higher IFN-g release than the control group but only difference of group 3 was significant (P<0.05). At day 300, group 1 showed significantly higher IFN-g release. No significant difference was observed at day 720. Using IFN-g release as a surrogate for vaccine efficacy, BCG plus a boost with CFP or CFPP combined with an adjuvant that improves cellular immune response has the potential to protect cattle against tuberculosis for moderate periods of time in vaccinated cattle under commercial settings.
10: Human genetics, 2010 Aug 17, 8(2)
IFNG +874 T>A single nucleotide polymorphism is associated with leprosy among Brazilians.
[Abstract]Leprosy is a chronic infectious disease caused by Mycobacterium leprae, a low virulence mycobacterium, and the outcome of disease is dependent on the host genetics for either susceptibility per se or severity. The IFNG gene codes for interferon-gamma (IFN-gamma), a cytokine that plays a key role in host defense against intracellular pathogens. Indeed, single nucleotide polymorphisms (SNPs) in IFNG have been evaluated in several genetic epidemiological studies, and the SNP +874T>A, the +874T allele, more specifically, has been associated with protection against infectious diseases, especially tuberculosis. Here, we evaluated the association of the IFNG locus with leprosy enrolling 2,125 Brazilian subjects. First, we conducted a case-control study with subjects recruited from the state of S?o Paulo, using the +874 T>A (rs2430561), +2109 A>G (rs1861494) and rs2069727 SNPs. Then, a second study including 1,370 individuals from Rio de Janeiro was conducted. Results of the case-control studies have shown a protective effect for +874T carriers (OR(adjusted) = 0.75; p = 0.005 for both studies combined), which was corroborated when these studies were compared with literature data. No association was found between the SNP +874T>A and the quantitative Mitsuda response. Nevertheless, the spontaneous IFN-gamma release by peripheral blood mononuclear cells was higher among +874T carriers. The results shown here along with a previously reported meta-analysis of tuberculosis studies indicate that the SNP +874T>A plays a role in resistance to mycobacterial diseases.
11: Anales de pediatria (Barcelona, Spain : 2003), 2010 Aug 10, 73(1)
[Myofibroblastic tumour, Mycobacterium avium infection and interferon-gamma pathway.]
[Abstract]A method for purification and refolding of recombinant human interferon-gamma (hIFNgamma) from inclusion bodies is described. It includes the following steps: (i) solubilization of inclusion bodies in 7.4 M guanidinium hydrochloride; (ii) purification of the denatured hIFNgamma by hydrophobic chromatography on Octyl-Sepharose column (one step elution with 6 M urea/1 M ammonium chloride); (iii) refolding of the partly purified protein in 0.75 M urea, 20 mM Tris-HCl, pH 8.2; (iv) purification of the refolded protein by CM-Sepharose chromatography. The protein thus obtained is characterized by the following general parameters: yield 1.0 mg/g wet cell mass; purity >99%; specific activity 2x10(8)IU/mg; stability - more than two years as a lyophilized powder and more than two months in solution at 4 degrees C.
12: Transplantation, 2010 Aug 6, 73(1)
CP-690550, a Janus Kinase Inhibitor, Suppresses CD4+ T-Cell-Mediated Acute Graft-Versus-Host Disease by Inhibiting the Interferon-gamma Pathway.
[Abstract]BACKGROUND.: Acute graft-versus-host disease (GVHD) is a critical obstacle to bone marrow transplantation. Although numerous studies have described immunosuppression protocols to mitigate acute GVHD, the need still exists for a more efficient immunosuppressant with fewer side effects. Here, we evaluated the protective effect of CP-690550, a newly developed Janus kinase inhibitor, in an acute GVHD model. METHODS.: CP-690550 was chemically synthesized. Acute GVHD was induced through the transfer of parent B6 (H-2) bone marrow and CD4 T cells into lethally irradiated (B6xbm12)F1 (H-2) mice. RESULTS.: CP-690550 treatments confined to days -3 to 11 of GVHD induction provided full protection against allogeneic, acute GVHD-related lethality and histopathology. An analysis of the initial donor-derived CD4 T-cell responses revealed that the inhibitory effects of CP-690550 were largely related to the suppression of donor CD4 T-cell-mediated interferon (IFN)-gamma production. Enhanced inhibition of T helper 1 cell differentiation, rather than the inhibition of allogeneic CD4 T-cell proliferation or T helper 17 cell differentiation, was also confirmed in allogeneic mixed lymphocyte reactions. Because lethality was considerably delayed by the systemic blockade of IFN-gamma, the principal protective effect of CP-690550 occurred through the modulation of IFN-gamma production. CONCLUSION.: The targeting of Janus kinase with a sensitive and specific inhibitor, CP-690550, conferred effective protection from acute GVHD induced by a semiallogeneic major histocompatibility complex class II-disparate combination. Protection from acute GVHD was largely mediated by the inhibition of IFN-gamma production.
13: Journal of cellular physiology, 2010 Jul 27, 76(2)
A novel anti-apoptotic role for apolipoprotein L2 in IFN-g-induced cytotoxicity in human bronchial epithelial cells.
[Abstract]Airway epithelium functions not only as a physical barrier, but also a regulator of lung inflammation. IFN-gamma plays a critical role in airway inflammation associated with respiratory viral infection. We investigated differential protein profiling in IFN-gamma-stimulated normal human bronchial epithelial cells (HBEC) using a 2-dimensional gel electrophoresis followed by MALDI-TOF-MS/MS. IFN-gamma markedly stimulated apolipoprotein L2 (ApoL2) protein expression in normal HBEC. ApoL2 mRNA expression was also elevated in normal human lung fibroblasts and smooth muscle cells stimulated with IFN-gamma, in lung tissues from an IFN-gamma-predominant influenza A virus-infected mouse lung injury model, and in cancer lung tissues from human patients. Normal HBEC showed strong resistance to IFN-gamma-induced cytotoxicity. ApoL2 knockdown by siRNA promoted IFN-gamma-induced cytotoxicity as revealed by a significant drop in cell viability using MTT and CyQUANT NF cell proliferation assays, and a marked increase in hypodiploid sub-G1 cell population in cell cycle analysis. Furthermore, depletion of ApoL2 facilitated IFN-gamma-induced membrane damage and chromatin condensation as observed in Hoechst and propidium iodide-double staining and in transmission electron microscopy, and DNA fragmentation using a DNA laddering assay, in a caspase-dependent manner. Our results reveal a novel function for ApoL2 in conferring anti-apoptotic ability of human bronchial epithelium to the cytotoxic effects of IFN-gamma, in maintaining airway epithelial layer integrity. (c) 2010 Wiley-Liss, Inc.
14: Journal of neuroscience research, 2010 Sep, 88(12)
Interferon-gamma inhibits central nervous system myelination through both STAT1-dependent and STAT1-independent pathways.
[Abstract]The immune cytokine interferon-gamma (IFN-gamma) plays a crucial role in immune-mediated demyelinating diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Our previous studies have shown that enforced expression of IFN-gamma in the central nervous system (CNS) inhibits developmental myelination or remyelination in EAE demyelinated lesions. Although many of the cellular actions of IFN-gamma result from its activation of the signal transducer and activator of transcription 1 (STAT1) pathway, recent studies have shown that STAT1-independent pathways regulate some facets of IFN-gamma biology. In this study, we dissected the role ofSTAT1-dependent and STAT1-independent pathways in IFN-gamma-induced hypomyelination using a genetic approach. We found that the induction of STAT1-dependent, IFN-gamma-responsive genes in response to this cytokine was abolished in the CNS of STAT1 null mice. Moreover, STAT1 deletion diminished oligodendrocyte loss, reduction of myelinated axons, and the inflammatory response in the CNS of transgenic mice that ectopically expressed IFN-gamma in the CNS. Nevertheless, IFN-gamma-induced reduction of myelin sheath thickness in the CNS of these mice was not altered by STAT1 deletion. Collectively, these data demonstrate that both STAT1-dependent and STAT1-independent pathways are involved in the detrimental effects of IFN-gamma on the myelination process. (c) 2010 Wiley-Liss, Inc.
15: Blood, 2010 Jul 19, 33(1)
Interferon gamma licensing of human dendritic cells in T helper-independent CD8+ alloimmunity.
[Abstract]The high frequency of allogeneic reactive CD8(+) T cells in human and their resistance to immunosuppression might be one of the reasons why successful tolerance-inducing strategies in rodents have failed in primates. Studies on the requirement for T-helper cells in priming CD8(+) T cells responses have led to disparate findings. Recent studies have reported CD8(+)-mediated allograft rejection independently of T-helper cells, however, the mechanisms that govern the activationn of these T cells are far from being elucidated. In this study, we demonstrated that LPS-treated DC were able to induce proliferation and cytotoxic activity of allogeneic CD8(+) T cells independently of CD4(+) T cells, while adding mycophenolic acid (MPA) to LPS abolished this capacity and resulted in anergic CD8(+) T cells that secreted high levels of IL-4, IL-5, IL-10 and TGF-beta. Interestingly, we demonstrated that MPA inhibited the LPS-induced synthesis of TNF-alpha, IL-12 and IFN-gamma in DC. Importantly, we found that adding exogenous IFN-gamma to MPA restored both the synthesis of cytokines and the ability to activate CD8(+) T cells. However, adding IL-12 or TNF-alpha had no effect. These results suggest that IFN-gamma has an important role in licensing DC to prime CD4-independent CD8 allogeneic T cells via an autocrine loop.
16: Immunity, 2010 Jul 23, 33(1)
Modular Utilization of Distal cis-Regulatory Elements Controls Ifng Gene Expression in T Cells Activated by Distinct Stimuli.
[Abstract]Distal cis-regulatory elements play essential roles in the T lineage-specific expression of cytokine genes. We have mapped interactions of three trans-acting factors-NF-kappaB, STAT4, and T-bet-with cis elements in the Ifng locus. We find that RelA is critical for optimal Ifng expression and is differentially recruited to multiple elements contingent upon T cell receptor (TCR) or interleukin-12 (IL-12) plus IL-18 signaling. RelA recruitment to at least four elements is dependent on T-bet-dependent remodeling of the Ifng locus and corecruitment of STAT4. STAT4 and NF-kappaB therefore cooperate at multiple cis elements to enable NF-kappaB-dependent enhancement of Ifng expression. RelA recruitment to distal elements was similar in T helper 1 (Th1) and effector CD8(+) T (Tc1) cells, although T-bet was dispensable in CD8 effectors. These results support a model of Ifng regulation in which distal cis-regulatory elements differentially recruit key transcription factors in a modular fashion to initiate gene transcription induced by distinct activation signals.
17: International journal of immunogenetics, 2010 Jul 18, 188(4)
Genomic structure and characterization of mRNA expression pattern of porcine interferon gamma receptor 1 gene.
[Abstract]Summary Interferon gamma receptor (IFNGR) plays an important role in the biological effects of IFN-gamma. In this study, porcine IFNGR1 cDNA was cloned and two transcripts both having a coding region of 1413 bp were identified. Porcine IFNGR1 cDNA shares 62.95%, 63.73%, 72.90% and 81.10% identity in nucleotide sequence; and 45.64%, 46.69%, 58.04% and 72.55% homology in amino acid sequence to those of rat, mouse, human and cattle, respectively. The porcine IFNGR1 genomic structure consists of seven exons and six introns and is located on porcine chromosome 1. The mRNA expression of porcine IFNGR1 gene is detected in all tissues examined, with strong expression in spleen and liver tissues and weak expression in cerebrum, cerebellum and uterus tissues, respectively. A different developmental pattern in IFNGR1 mRNA expression between Laiwu and Duroc breeds was revealed by real-time quantitative RT-PCR: in Duroc pigs, a significantly higher expression was found in the tissues of heart (P < 0.05), liver (P < 0.01), kidney (P < 0.01) and skeletal muscle (P < 0.05) of adult pigs compared to piglets. In porcine reproductive and respiratory syndrome virus (PRRSV)-infected Dapulian pigs, compared to the uninfected ones, the expression level of IFNGR1 mRNA in spleen was significantly up-regulated (P < 0.05), whereas its expression in the lymph node was significantly down-regulated (P < 0.05); in PRRSV-infected Duroc x Yorkshire x Landrace commercial pigs, however, the differences both in spleen and lymph node tissues were not significant.
18: Immunology, 2010 Jul 16, 188(4)
GATA-binding protein-3 regulates T helper type 2 cytokine and ifng loci through interaction with metastasis-associated protein 2.
[Abstract]Summary GATA-binding protein-3 (GATA-3) regulates the T helper type 2 (Th2) cytokine locus through induction of chromatin remodelling. However, the molecular mechanism for this is poorly understood. To understand this mechanism better, we screened GATA-3 interacting proteins using affinity purification and mass spectrometry. We found that GATA-3 bound to metastasis-associated protein 2 (MTA-2), a component of the NuRD chromatin remodelling complex. GATA-3 and MTA-2 in turn bound to several regulatory regions of the Th2 cytokine locus and the ifng promoter. Cell transfection assay showed that MTA-2 acted as an antagonist with GATA-3 in the expression of Th2 cytokines, but co-operated with GATA-3 in the repression of the ifng gene expression. These results suggest that GATA-3 interacts with MTA-2 to co-ordinately regulate Th2 cytokine and ifng loci during T helper cell differentiation.
19: Fish & shellfish immunology, 2010 Jul 12, 188(4)
Functional analysis of carp interferon-gamma: Evolutionary conservation of classical phagocyte activation.
[Abstract]In teleost fish two IFN-gamma gene sequences were found for which two phylogenetic clusters can be distinguished. Our previous analysis of expression of these in carp led us to hypothesize that a classical IFN-gamma function is associated with the IFN-gamma2 cluster. We investigated the evolutionary conservation of the IFN-gamma function, inducing classical activation of phagocytes, thus skewing towards a Th1-like profile of immune activation. Recombinant proteins for the carp IFN-gamma sequences of both clusters were made and we studied their effects on expression of proinflammatory mediators. Carp IFN-gamma2, in contrast to carp IFN-gamma1, was powerful in inducing a proinflammatory reaction in phagocytes: a classical synergistic response with lipopolysaccharide was observed for the induction of iNOS expression and NO release, for expression of CXCL9-11-like chemokines and the expression of proinflammatory cytokines IL-1beta, TNFalpha and the IL-12 subunits p35 and p40. In contrast, like in mammals, the CXCL8-like cytokines are LPS but not IFN-gamma sensitive. These results corroborate an evolutionary conserved nature of IFN-gamma function in lower vertebrates including classical activation of phagocytes.
20: International immunopharmacology, 2010 Jul 12, 188(4)
Promotion of interferon-gamma production by natural killer cells via suppression of murine peritoneal macrophage prostaglandin E(2) production using intravenous anesthetic propofol.
[Abstract]Propofol is an intravenous anesthetic, widely used for general anesthesia during surgery, which inevitably involves tissue trauma with inflammation. At sites of inflammation, prostanoids, especially prostaglandin E(2) (PGE(2)), are abundant. This study addresses the effect of propofol on macrophage PGE(2) production. Using thioglycollate-elicited murine peritoneal macrophages, propofol (7.5-30muM) suppressed lipopolysaccharide-induced PGE(2) production. The suppression was via the direct inhibition of cyclooxygenase (COX) enzyme activity and due neither to the downregulation of COX expression nor the inhibition of arachidonic acid release from plasma membranes. In macrophage:natural killer (NK) cell co-culture, propofol dramatically increased interferon-gamma (IFN-gamma) production, and the actions of propofol were mimicked by a selective COX-2 inhibitor, NS-398, as well as the selective EP4 receptor antagonist L-161,982, suggesting a role of PGE(2) suppression in the upregulation of IFN-gamma production. Furthermore, in purified NK cell culture, PGE(2) directly suppressed the production of IFN-gamma by activated NK cells, which was reversed by selective inhibition of EP4 activity. Taken together, our results show that, in macrophage:NK cell co-culture, propofol, through the suppression of macrophage PGE(2) production, upregulates NK cell IFN-gamma production by alleviating EP4 receptor-mediated suppression of IFN-gamma production. Propofol may potentially exert considerable influence on inflammation and immunity by suppressing PGE(2) synthesis.
21: Journal of leukocyte biology, 2010 Jul 13, 188(4)
The role of interferon-{gamma} in the pathogenesis of acute intra-abdominal sepsis.
[Abstract]Several studies indicate that IFN-gamma facilitates systemic inflammation during endotoxin-induced shock. However, the pathobiology of IFN-gamma in clinically relevant models of septic shock, such as CLP, is not well understood. In this study, the role of IFN-gamma in the pathogenesis of CLP-induced septic shock was evaluated by examining IFN-gamma production at the tissue and cellular levels. The impact of IFN-gamma neutralization on systemic inflammation, bacterial clearance, and survival was also determined. Following CLP, concentrations of IFN-gamma in plasma and peritoneal lavage fluid were low in comparison with concentrations of IL-6 and MIP-2, as was IFN-gamma mRNA expression in liver and spleen. The overall percentage of IFN-gamma(+) splenocytes was <5% after CLP and not statistically different from control mice. Intracellular IFN-gamma was present in a large proportion of peritoneal exudate cells after CLP, primarily in infiltrating myeloid cells and NK cells. i.p. myeloid cell activation was decreased in IFN-gammaKO mice, and plasma concentrations of IL-6 and MIP-2 were significantly lower in IFN-gammaKO mice and in mice treated with anti-IFN-gamma compared with controls, but bacterial clearance was not affected. IFN-gammaKO mice were resistant to CLP-induced mortality when treated with systemic antibiotics. However, neutralization of IFN-gamma with blocking antibodies did not improve survival significantly. These studies show that IFN-gamma facilitates the proinflammatory response during CLP-induced septic shock. However, neutralization of IFN-gamma did not improve survival uniformly.
22: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2010 Jul 13, 188(4)
Predominant Interferon-gamma-Mediated Expression of CXCL9, CXCL10, and CCL5 Proteins in the Brain During Chronic Infection with Toxoplasma gondii in BALB/c Mice Resistant to Development of Toxoplasmic Encephalitis.
[Abstract]We examined the role of interferon-gamma (IFN-gamma) in expression of chemokine mRNA and proteins in the brain during chronic infection with Toxoplasma gondii using BALB/c and BALB/c-background IFN-gamma knockout (IFN-gamma(-/-)) mice. BALB/c mice are genetically resistant to development of toxoplasmic encephalitis and establish a latent, chronic infection in the brain through IFN-gamma-mediated immune responses. Amounts of mRNA for CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC, CCL2/MCP-1, CCL3/MIP-1alpha, and CCL5/RANTES significantly increased in the brains of wild-type mice after infection. CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES mRNA were most abundant among these chemokines. An increase in amounts of mRNA for CXCL10/IP-10, CCL2/MCP-1, CCL3/MIP-1alpha, and CCL5/RANTES was also observed in the brains of IFN-gamma(-/-) mice after infection, although CXCL10/I-10 and CCL5/RANTES mRNA levels in infected IFN-gamma(-/-) mice were significantly lower than those of infected wild-type animals. Amounts of mRNA for CXCL9/MIG and CXCL11/I-TAC remained at the basal levels in infected IFN-gamma(-/-) mice. When amounts of the chemokine proteins were examined in the brain homogenates of uninfected and infected mice of both strains, large amounts of CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES were detected only in infected wild-type animals. These results indicate that CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES are the chemokines predominantly induced in the brains of genetically resistant BALB/c mice during chronic infection with T. gondii, and their expression is dependent on IFN-gamma.
23: AIDS research and human retroviruses, 2010 Jul 12, 188(4)
Clearance of HIV Type 1 Envelope Recombinant Sendai Virus Depends on CD4(+) T Cells and Interferon-gamma But Not B Cells, CD8(+) T Cells, or Perforin.
[Abstract]Abstract T cell-mediated viral clearance is classically attributed to the CD8(+) T cell subset, but CD4(+) T cells can sometimes assume this role. One such instance was illustrated by the immunization of C57BL/6 mice with HIV-1 envelope, followed by challenge with a recombinant Sendai virus (rSeV-env) carrying a gene for secreted HIV-1 envelope protein. Vaccinated mice that lacked both B cells (muMT) and CD8(+) T cells controlled virus, but control was lost when CD4(+) T cells were depleted. To explain this activity, we questioned whether CD4(+) T cells might utilize perforin for killing of MHC class II-positive targets. We also asked if the process might depend on IFN-gamma, which can upregulate MHC expression and enhance T cell recruitment to sites of virus challenge. To address these possibilities, we vaccinated perforin-KO mice with HIV-1 envelope and challenged them with rSeV-env. We found that perforin was not required for (1) CD4(+) T cell homing to the site of virus challenge, (2) expression of Th1 and Th2 cytokines (including IFN-gamma), or (3) virus clearance. To determine if IFN-gamma was required for protection, we repeated experiments in IFN-gamma-KO animals. In this case, significant protection was lost, although the CD4(+) T cells trafficked readily to the site of infection. In fact, local CD4(+) T cell numbers in vaccinated IFN-gamma- KO mice exceeded those in wild type animals. In both cases, cells were alphass TCR(+), NK-1.1(-), and CD44(+), typifying an activated CD4(+) T cell subset. Taken together, our results showed that HIV-1 envelope recombinant virus clearance was dependent on CD4(+) T cells and IFN-gamma, but occurred in the absence of B cells, CD8(+) T cells, or perforin.
24: Plasmid, 2010 Jul 8, 188(4)
Replicative and integrative plasmids for production of human interferon gamma in Bacillus subtilis.
[Abstract]Integrative and replicative plasmids for the expression driven by the P(43) promoter and secretion of recombinant proteins in Bacillus subtilis were constructed. The plasmids named pInt and pRep respectively were tested for the production of recombinant human interferon gamma (rhIFN-gamma. A synthetic hIFN-gamma gene employing the optimized B. subtilis codon-usage was fused with the Bacillus licheniformis alpha-amylase signal peptide (sp-amyL) encoding sequence. The integrative construct produced 2.5+/-0.2 mg l(-1) and the replicative system produced 20.3+/-0.8 mg l(-1) of total recombinant rhIFN-gamma . The results showed that secretion of hIFN-gamma was the bottleneck for the overexpression of mature rhIFN-gamma by B. subtilis.
25: The Pediatric infectious disease journal, 2010 Jul 7, 30(27)
WHOLE BLOOD INTERFERON-gamma RELEASE ASSAY IS A USEFUL TOOL FOR THE DIAGNOSIS OF TUBERCULOSIS INFECTION PARTICULARLY AMONG BACILLE CALMETTE GUERIN-VACCINATED CHILDREN.
[Abstract]The performance of QuantiFERON-tuberculosis (TB) Gold-In-Tube assay was compared with the tuberculin skin test for the diagnosis of TB among children. It was shown that among non-Bacille Calmette Gu¨¨rin immunized children, agreement between tests was excellent both in those with TB disease and in TB contacts. Among Bacille Calmette Gu¨¨rin-immunized children, agreement was fair in those with active disease and poor among TB contacts. It is concluded that QuantiFERON-TB Gold-In-Tube compares with the tuberculin skin test in the diagnosis of TB disease and latent tuberculosis infection in TB contacts among children and has enhanced specificity.
26: Journal of leukocyte biology, 2010 Jul 7, 41(4)
Interferon-{gamma}--central mediator of protective immune responses against the pre-erythrocytic and blood stage of malaria.
[Abstract]Immune responses against Plasmodium parasites, the causative organisms of malaria, are traditionally dichotomized into pre-erythrocytic and blood-stage components. Whereas the central role of cellular responses in pre-erythrocytic immunity is well established, protection against blood-stage parasites has generally been ascribed to humoral responses. A number of recent studies, however, have highlighted the existence of cellular immunity against blood-stage parasites, in particular, the prominence of IFN-gamma production. Here, we have undertaken to chart the contribution of this prototypical cellular cytokine to immunity against pre-erythrocytic and blood-stage parasites. We summarize the various antiparasitic effector functions that IFN-gamma serves to induce, review an array of data about its protective effects, and scrutinize evidence for any deleterious, immunopathological outcome in malaria patients. We discuss the activation and contribution of different cellular sources of IFN-gamma production during malaria infection and its regulation in relation to exposure. We conclude that IFN-gamma forms a central mediator of protective immune responses against pre-erythrocytic and blood-stage malaria parasites and identify a number of implications for rational malaria vaccine development.
27: The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010 Jul 7, 30(27)
Endogenous interferon gamma directly regulates neural precursors in the non-inflammatory brain.
[Abstract]Although a number of growth factors have been shown to be involved in neurogenesis, the role of inflammatory cytokines remains relatively unexplored in the normal brain. Here we investigated the effect of interferon gamma (IFNgamma) in the regulation of neural precursor (NP) activity in both the developing and the adult mouse brain. Exogenous IFNgamma inhibited neurosphere formation from the wild-type neonatal and adult subventricular zone (SVZ). More importantly, however, these effects were mirrored in vivo, with mutant mice lacking endogenous IFNgamma displaying enhanced neurogenesis, as demonstrated by an increase in proliferative bromodeoxyuridine-labeled cells in the SVZ and an increased percentage of newborn neurons in the olfactory bulb. Furthermore, NPs isolated from IFNgamma null mice exhibited an increase in self-renewal ability and in the capacity to produce differentiated neurons and oligodendrocytes. These effects resulted from the direct action of IFNgamma on the NPs, as determined by single-cell assays and the fact that nearly all the neurospheres were derived from cells positive for major histocompatibility complex class I antigen, a downstream marker of IFNgamma-mediated activation. Moreover, the inhibitory effect was ameliorated in the presence of SVZ-derived microglia, with their removal resulting in almost complete inhibition of NP proliferation. Interestingly, in contrast to the results obtained in the adult, exogenous IFNgamma treatment stimulated neurosphere formation from the embryonic brain, an effect that was mediated by sonic hedgehog. Together these findings provide the first direct evidence that IFNgamma acts as a regulator of the active NP pool in the non-inflammatory brain.
28: Scandinavian journal of infectious diseases, 2010 Jul 7, 30(27)
Diagnostic usefulness of enzyme-linked immunospot assay for interferon-gamma for tuberculosis in cancer patients.
[Abstract]Abstract The interferon-gamma enzyme-linked immunospot assay (ELISPOT) has been demonstrated to be useful in the diagnosis of active tuberculosis (TB). In this study we aimed to evaluate the diagnostic performance of the ELISPOT assay in cancer patients with suspected pulmonary TB. Eighty-one cancer patients with suspected pulmonary TB were prospectively enrolled from April 2007 to December 2008, to investigate the diagnostic sensitivity and specificity of the ELISPOT assay. Of the 38 patients with TB, 33 (86.8%) had positive ELISPOT results. Of the 43 patients without TB, the results of the ELISPOT assay were negative in 35 (81.3%) patients. The overall sensitivity was 86.8%, specificity 81.3%, positive predictive value 80.5% and negative predictive value 87.5%. No significant difference was noted for the diagnostic performance of the ELISPOT assay for diagnosing TB between solid cancer and haematological cancer patients. In addition, a quantitative study did not show that TB patients with solid cancers have a better response than haematological cancer patients as measured by spot-forming cells per 10(6) peripheral blood mononuclear cells after exposure to early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10). In conclusion, the ELISPOT assay could be a useful supplementary tool for the diagnosis of pulmonary TB among cancer patients, irrespective of cancer type.
29: Scandinavian journal of infectious diseases, 2010 Jul 7, 30(27)
Evaluation of a modified interferon-gamma release assay for the diagnosis of latent tuberculosis infection in adult and paediatric populations that enables delayed processing.
[Abstract]Abstract The objective of the study was to evaluate the specificity of a modified interferon-gamma release assay (IGRA) procedure that allows storage of blood samples for up to 32 h before processing. A total of 116 subjects were enrolled in the study. Two blood samples were collected from each volunteer; 1 specimen was processed within 8 h and analyzed using the T-SPOT((R)).TB test and the second specimen was stored overnight and processed 23-32 h later after addition of the T-Cell Xtend reagent and then analyzed using the T-SPOT.TB test. A total of 108 paired T-SPOT.TB and T-SPOT.TB plus T-Cell Xtend tests were analyzed on specimens from 97 adults and 11 children. The median age of the subjects was 28 y with 68.5% female and 78.7% white. The overall agreement between the 2 tests was 98.2% (106/108). The specificity of the T-SPOT.TB test was 99.1% (107/108) and for T-SPOT.TB plus T-Cell Xtend was 97.2%. The 2 tests were comparable in results. Increasing storage time of the collected blood specimen prior to processing provides flexibility for clinicians and laboratories. Additional studies in larger and diverse patient populations including immunocompromised and paediatric patients, and patients with active TB disease or latent tuberculosis infection are needed.
30: Veterinary research communications, 2010 Jul 6, 41(4)
The correlations among serum tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and sialic acids with peripheral lymphocytes in bovine tropical theileriosis.
[Abstract]The infection with protozoan parasite Theileria annulata induces changes triggering the activation and/or proliferation of the host lymphocytes. In order to find out the possible correlations among peripheral circulatory lymphocytes, cytokine activities and the level of sialic acids, 50 dairy Holstein cattle, naturally infected with T. annulata, were divided into 4 subgroups according to their parasitemia rates (<1%, 1-3%, 3-5% and >5%). Also, ten non-infected cattle were sampled as control group. Blood samples were taken from jugular vein into acid citrate dextrose-containing tubes for measuring hematological parameters and B and T (CD(4) and CD(8)) cell populations and without anticoagulant for TNF-alpha, IFN-gamma and sialic acid concentrations. Remarkable decreases observed in red blood cells (RBCs), white blood cells (WBCs) and packed cell volume (PCV) in infected cattle compared to healthy ones (P < 0.05). Also, with increase in parasitemia rate, total lymphocytes and monocytes alleviated in the diseased groups. By contrast, total neutrohpils and the concentrations of TNF-alpha, IFN-gamma and total sialic acids were significantly elevated (P < 0.05) in infected animals. Accordingly, the circulatory populations of CD(4) and CD(8) T cells and B cells showed a substantial decrease, while a significant increase was observed in T (CD(4) and CD(8)) cells in cattle infected with <1% parasitemia rates. Decreased circulatory T cell population shows the ineffective responses of T cells to the stimulatory cytokines such as IFN-gamma or TNF-alpha. On the other hand, the elevation of cytokines (particularly IFN-gamma) and sialic acids have presumably an inhibitory role on circulatory B cell population in infected cattle. In addition, a high level of sialic acid concentration indicates the probable role of sialic acid to regulate the parasite-host cell adhesion during sporozoites invasion.
31: Gut, 2010 Jun 29, 358(1-2)
Interferon {gamma} receptor 2 gene variants are associated with liver fibrosis in patients with chronic hepatitis C infection.
[Abstract]Background Only a minority of patients with chronic hepatitis C virus (HCV) infection develops severe liver fibrosis, a process that may be controlled by human genetic factors. Objective To investigate the role of 384 single nucleotide polymorphisms (SNPs) located in 36 candidate genes related to the fibrogenesis/fibrolysis process. Methods Patients with chronic HCV infection were gathered from two French cohorts (prospectively and retrospectively). The overall sample consisted of 393 HCV-infected subjects without known risk factors for fibrosis progression, including 134 patients with severe liver fibrosis and 259 without severe fibrosis. Results Only two SNPs in strong linkage disequilibrium (LD) in the interferon gamma receptor 2 gene (IFNGR2) were significantly associated with liver fibrosis in both the prospective and the retrospective samples. The strongest association (p=8x10(-5)) was observed with the G/A SNP rs9976971 with an OR of severe fibrosis for AA versus AG or GG subjects at 2.95 (95% CI 1.70 to 5.11). This effect was higher (p=9x10(-7)) when taking into account the time of follow-up, and the hazard ratio of progression towards severe fibrosis for AA patients was 2.62 (1.76 to 3.91). Refined sequencing and analysis of the IFNGR2 region identified two additional variants in strong LD with rs9976971. No haplotypes derived from this cluster of four variants provided stronger evidence for association than rs9976971 alone. Conclusions This identification of a cluster of four IFNGR2 variants strongly associated with fibrosis progression in chronic HCV infection underlines the role of IFNgamma in the development of liver fibrosis that may pave the way for new treatments.
32: Journal of medical genetics, 2010 Jun 28, 358(1-2)
Multiple cutaneous squamous cell carcinomas in a patient with interferon {gamma} receptor 2 (IFN{gamma}R2) deficiency.
[Abstract]Disseminated squamous cell carcinoma (SCC) of the skin is exceedingly rare in children. SCC occurs after immunodeficiency from immunosuppression in organ transplant recipients or patients with HIV infection or leukaemia, but has not been reported in primary immunodeficiencies other than epidermodysplasia verruciformis. Interferon gamma receptor 2 (IFNgammaR2) deficiency is an exceedingly rare primary immunodeficiency, conferring almost selective predisposition to mycobacterial diseases. A disseminated, cutaneous SCC is described that occurred in a patient homozygous for a novel frameshift deletion at positions 949 and 950 (949delTG) in the IFNGR2 gene. The patient first presented at 1 year of age with disseminated Mycobacterium avium infection, with later infections of atypical mycobacteria (Mycobacterium fortuitum and Mycobacterium porcium). At 17 years of age, the patient developed multifocal SCC lesions on the face and both hands. Histopathological examination revealed well differentiated SCC. Despite local tumour excision, multiple lesions occurred and a large SCC on the right arm required amputation. The patient died at 20 years of age of disseminated SCC. Inherited disorders of IFNgamma mediated immunity may predispose patients to SCC.
33: MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control, 2010 Jun 25, 59(RR-5)
Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection --- United States, 2010.
[Abstract]n 2005, CDC published guidelines for using the QuantiFERON-TB Gold test (QFT-G) (Cellestis Limited, Carnegie, Victoria, Australia) (CDC. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR;54[No. RR-15]:49--55). Subsequently, two new interferon gamma (IFN- ?) release assays (IGRAs) were approved by the Food and Drug Administration (FDA) as aids in diagnosing M. tuberculosis infection, both latent infection and infection manifesting as active tuberculosis. These tests are the QuantiFERON-TB Gold In-Tube test (QFT-GIT) (Cellestis Limited, Carnegie, Victoria, Australia) and the T-SPOT.TB test (T-Spot) (Oxford Immunotec Limited, Abingdon, United Kingdom). The antigens, methods, and interpretation criteria for these assays differ from those for IGRAs approved previously by FDA. For assistance in developing recommendations related to IGRA use, CDC convened a group of experts to review the scientific evidence and provide opinions regarding use of IGRAs. Data submitted to FDA, published reports, and expert opinion related to IGRAs were used in preparing these guidelines. Results of studies examining sensitivity, specificity, and agreement for IGRAs and TST vary with respect to which test is better. Although data on the accuracy of IGRAs and their ability to predict subsequent active tuberculosis are limited, to date, no major deficiencies have been reported in studies involving various populations. This report provides guidance to U.S. public health officials, health-care providers, and laboratory workers for use of FDA-approved IGRAs in the diagnosis of M. tuberculosis infection in adults and children. In brief, TSTs and IGRAs (QFT-G, QFT-GIT, and T-Spot) may be used as aids in diagnosing M. tuberculosis infection. They may be used for surveillance purposes and to identify persons likely to benefit from treatment. Multiple additional recommendations are provided that address quality control, test selection, and medical management after testing. Although substantial progress has been made in documenting the utility of IGRAs, additional research is needed that focuses on the value and limitations of IGRAs in situations of importance to medical care or tuberculosis control. Specific areas needing additional research are listed. s.
34: Parasitology research, 2010 Jun 24, 358(1-2)
The DNA-induced protective immunity with chicken interferon gamma against poultry coccidiosis.
[Abstract]The immunogenicity of Eimeria acervulina cSZ-2 and chicken interferon gamma was observed against Eimeria tenella challenge. The chickens were randomly divided into six groups of 24 chicks each. Three groups of chickens were injected with DNA vaccines pVAX1-cSZ2, pVAX1-chIFN-gamma and pVAX1-cSZ2-chIFN-gamma two times (at days 14 and 21) at a dose of 100 microg intramuscularly. Three other groups were kept as control and injected with TE buffer (10 mM Tris-HCl pH 7.6 and 1 mM EDTA). One week following the booster dose, all chickens except the non-infected, non-vaccinated control group were inoculated orally with 5 x 10(4) sporulated oocysts of E. tenella. Seven days post challenge, all chickens were weighted and slaughtered for cecal lesion scoring and oocyst counts. The results demonstrated that cSZ-2 in combination with interferon gamma can protect chickens from coccidiosis by significantly decreasing body weight loss and oocyst excretion reflecting partial protection against E. tenella infection, and further studies are necessary to test for protection against other Eimeria species.
35: Journal of immunology (Baltimore, Md. : 1950), 2010 Jun 23, 358(1-2)
Distal Regions of the Human IFNG Locus Direct Cell Type-Specific Expression.
[Abstract]Genes, such as IFNG, which are expressed in multiple cell lineages of the immune system, may employ a common set of regulatory elements to direct transcription in multiple cell types or individual regulatory elements to direct expression in individual cell lineages. By employing a bacterial artificial chromosome transgenic system, we demonstrate that IFNG employs unique regulatory elements to achieve lineage-specific transcriptional control. Specifically, a one 1-kb element 30 kb upstream of IFNG activates transcription in T cells and NKT cells but not in NK cells. This distal regulatory element is a Runx3 binding site in Th1 cells and is needed for RNA polymerase II recruitment to IFNG, but it is not absolutely required for histone acetylation of the IFNG locus. These results support a model whereby IFNG utilizes cis-regulatory elements with cell type-restricted function.
36: Journal of virology, 2010 Jun 23, 358(1-2)
Interferon-{alpha} and not Interferon-{gamma} inhibit Salmonid Alphavirus subtype-3 replication in vitro.
[Abstract]Salmonid alphavirus (SAV) is an emerging virus in salmonid aquaculture with SAV-3 being the only subtype found in Norway. Until now there has been little focus on interferon (IFN)-alpha-induced antiviral responses during virus infection in vivo or in vitro in fish. The possible involvement of IFNgamma in response to SAV-3 is also not known. In this study the two IFNs were cloned and expressed as recombinant proteins (rIFNalpha and IFNgamma) and used for in vitro studies. SAV-3 infection in a permissive salmon cell line (TO cells) results in IFN-alpha and ISGs gene mRNA upregulation. Preinfection treatment (4 to 24h prior to infection) with salmon rIFN-alpha induces an antiviral state that inhibits the replication of SAV-3 and protects the cells against virus induced cytopathic effect (CPE). The antiviral state coincides with a strong expression of Mx and ISG15 gene mRNA and Mx protein expression. When rIFN-alpha is administered at time of infection and up to 24h postinfection virus replication is not inhibited and cells are not protected against virus-induced CPE. By 40 h postinfection eIF2alpha is phosphorylated concomitant with expression of the E2 protein as assessed by western blot. Postinfection treatment with rIFN-alpha results in moderate reduction in E2 expression in accordance with moderate downregulation of cellular protein synthesis, around 65% reduction by 60h postinfection. rIFNgamma only has minor inhibitory effect on SAV-3 replication in vitro. SAV-3 is sensitive to the preinfection antiviral state induced by rIFN-alpha while postinfection antiviral responses or postinfection treatment with rIFN-alpha is not able to limit viral replication.
37: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2010 Jun 22, 358(1-2)
Anti-Asthma Simplified Herbal Medicine Intervention-induced long-lasting tolerance to allergen exposure in an asthma model is interferon-gamma, but not transforming growth factor-beta dependent.
[Abstract]Summary Background Chronic allergic asthma is the result of a T-helper type 2 (Th2)-biased immune status. Current asthma therapies control symptoms in some patients, but a long-lasting therapy has not been established. Anti-Asthma Simplified Herbal Medicine Intervention (ASHMI()), a Chinese herbal formula improved symptoms and lung function, and reduced Th2 responses in a controlled trial of patients with persistent moderate to severe asthma. Objective We evaluated the persistence of ASHMI() beneficial effects following therapy in a murine model of chronic asthma and the immunological mechanisms underlying such effects. Methods BALB/c mice sensitized intraperitoneally with ovalbumin (OVA) received 3 weekly intratracheal OVA challenges to induce airway hyper-reactivity (AHR) and inflammation (OVA mice). Additionally, OVA mice were treated with ASHMI() (OVA/ASHMI()) or water (OVA/sham) for 4 weeks, and then challenged immediately and 8 weeks post-therapy. In other experiments, OVA mice received ASHMI() treatment with concomitant neutralization of IFN-gamma or TGF-beta. Effects on airway responses, cytokine- and OVA-specific IgE levels were determined 8 weeks post-therapy. Results Before treatment, OVA mice exhibited AHR and pulmonary eosinophilic inflammation following OVA challenge, which was almost completely resolved immediately after completing treatment with ASHMI() and did not re-occur following OVA re-challenge up to 8 weeks post-therapy. Decreased allergen-specific IgE and Th2 cytokine levels, and increased IFN-gamma levels also persisted at least 8 weeks post-therapy. ASHMI() effects were eliminated by the neutralization of IFN-gamma, but not TGF-beta, during therapy. Conclusion ASHMI() induced long-lasting post-therapy tolerance to antigen-induced inflammation and AHR. IFN-gamma is a critical factor in ASHMI() effects.
38: Mammalian genome : official journal of the International Mammalian Genome Society, 2010 Jun 22, 358(1-2)
Mapping of quantitative trait loci for mycoplasma and tetanus antibodies and interferon-gamma in a porcine F(2) Duroc x Pietrain resource population.
[Abstract]The aim of the present study was to detect quantitative trait loci (QTL) for innate and adaptive immunity in pigs. For this purpose, a Duroc x Pietrain F(2) resource population (DUPI) with 319 offspring was used to map QTL for the immune traits blood antibodies and interferon-gamma using 122 microsatellites covering all autosomes. Antibodies response to Mycoplasma hyopneumoniae and tetanus toxoid vaccine and the interferon-gamma (IFNG) serum concentration were measured at three different time points and were used as phenotypes. The differences of antibodies and interferon concentration between different time points were also used for the linkage mapping. Line-cross and imprinting QTL analysis, including two-QTL, were performed using QTL Express. A total of 30 QTL (12, 6, and 12 for mycoplasma, tetanus antibody, and IFNG, respectively) were identified at the 5% chromosome-wide-level significant, of which 28 were detected by line-cross and 2 by imprinting model. In addition, two QTL were identified on chromosome 5 using the two-QTL approach where both loci were in repulsion phase. Most QTL were detected on pig chromosomes 2, 5, 11, and 18. Antibodies were increased over time and immune traits were found to be affected by sex, litter size, parity, and month of birth. The results demonstrated that antibody and IFNG concentration are influenced by multiple chromosomal areas. The flanking markers of the QTL identified for IFNG on SSC5 did incorporate the position of the porcine IFNG gene. The detected QTL will allow further research in these QTL regions for candidate genes and their utilization in selection to improve the immune response and disease resistance in pig.
39: PloS one, 2010, 5(6)
Interferon-gamma Produced by Microglia and the Neuropeptide PACAP Have Opposite Effects on the Viability of Neural Progenitor Cells.
[Abstract]Inflammation is part of many neurological disorders and immune reactions may influence neuronal progenitor cells (NPCs) contributing to the disease process. Our knowledge about the interplay between different cell types in brain inflammation are not fully understood. It is important to know the mechanisms and factors involved in order to enhance regeneration and brain repair. We show here that NPCs express receptors for interferon-gamma (IFNgamma), and IFNgamma activates the signal transducer and activator of transcription (STAT) protein-1. IFNgamma reduced cell proliferation in NPCs by upregulation of the cell cycle protein p21 as well as induced cell death of NPCs by activating caspase-3. Studies of putative factors for rescue showed that the neuropeptide, Pituitary adenylate cyclase-activating polypeptide (PACAP) increased cell viability, the levels of p-Bad and reduced caspase-3 activation in the NPCs. Medium from cultured microglia contained IFNgamma and decreased the viability of NPCs, whilst blocking with anti-IFNgamma antibodies counteracted this effect. The results show that NPCs are negatively influenced by IFNgamma whereas PACAP is able to modulate its action. The interplay between IFNgamma released from immune cells and PACAP is of importance in brain inflammation and may affect the regeneration and recruitment of NPCs in immune diseases. The observed effects of IFNgamma on NPCs deserve to be taken into account in human anti-viral therapies particularly in children with higher rates of brain stem cell proliferation.
40: Microbial pathogenesis, 2010 Jun 14, 358(1-2)
Analysis of modulated gene expression in a model of Interferon-gamma-induced persistence of Chlamydia trachomatis in HEp-2 cells.
[Abstract]BACKGROUND: Chlamydia trachomatis is an important pathogen, being the commonest sexually transmitted bacterial disease in the Western world and is also implicated in a number of acute and chronic diseases. Persistent infections of C. trachomatis are particularly associated with chronic infections, which although eliciting an immune response, result in tissue damage leading to complications such as pelvic inflammatory disease. Interferon (IFN)-gamma is known to induce persistent infections of C. trachomatis both in vitro and in vivo. METHODS: A model of IFN-gamma-induced persistence containing aberrant inclusions of C. trachomatis was developed in the HEp-2 cell line. Morphological changes to inclusions were assessed by fluorescence immunocytochemistry and transcript levels determined by Real-Time RT-PCR. To assess infectivity of C. trachomatis in an IFN-gamma-induced persistent state, cultures containing aberrant inclusions were inoculated onto fresh HEp-2 monolayers. RESULTS: IFN-gamma induced aberrant inclusion formation at 0.01ng/ml. Doses from 0.05-100ng/ml did not significantly increase numbers of aberrant inclusions, and some normal inclusions were observed at the highest dose of IFN-gamma. Transfer of IFN-gamma-treated C. trachomatis onto fresh cultures confirmed the infectivity of these cultures. Real-Time RT-PCR identified apparent increased expression of the C. trachomatis heat-shock response genes ct604 and ct755 at 96-h post-infection. However comparisons with control cultures suggest that this more likely reflects a failure to down-regulate gene expression as observed in untreated cultures. CONCLUSIONS: These data show that whereas IFN-gamma induces aberrant inclusion formation, many normal inclusions are still observed at high doses of IFN-gamma, and that the infectivity of such cultures is presumably from these. Transcriptional changes observed in response to IFN-gamma suggest a failure of the C. trachomatis life cycle in response to IFN-gamma, however IFN-gamma induced transcriptional changes may be masked by the presence of normal inclusions. The implications of these observations in relation to models of persistence of C. trachomatis are discussed.
41: Archives of disease in childhood, 2010 Jun 16, 358(1-2)
Diagnostic performance of interferon {gamma} may be site specific.
[Abstract]Iterative affinity selection procedures were used to isolate a number of single chain Fv (scFv) antibody fragment clones from na?ve Tomlinson I+J phage display libraries that specifically recognize and bind a chemokine, monokine induced by interferon-gamma (MIG/CXCL9). MIG is an important transplant rejection/biology chemokine protein. ELISA-based affinity characterization results indicate that selectants preferentially bind to MIG in the presence of key biopanning component materials and closely related chemokine proteins. These novel antibody fragments may find utility as molecular affinity interface receptors in various electrochemical biosensor platforms to provide specific MIG binding capability with potential applications in transplant rejection monitoring, and other biomedical applications where detection of MIG level is important.
42: European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2010 Jun 11, 358(1-2)
Association of genetic polymorphisms in the IL12-IFNG pathway with susceptibility to and prognosis of pulmonary tuberculosis in a Chinese population.
[Abstract]Cytokines are crucial in activation of the cell-mediated immunity required for eliminating pathogens and controlling intracellular growth of Mycobacterium tuberculosis (TB). Genetic variants in the IL12-IFNG axis are hypothesized to be involved in the development and progression of TB. Genetic polymorphisms of rs2243115 and rs568408 in IL12A, rs3212227 in IL12B and rs2430561 in IFNG(+874) were detected in 522 pulmonary TB cases and 527 controls recruited from Yangzhong and Wujin County of China. It was found that genetic variants TG/GG of rs2243115(IL12A) were associated with a decreased risk of TB, with odds ratio (95% confidence interval) of 0.70 (0.49-0.99), whereas variant genotypes AT/TT of rs2430561(IFNG) conferred 82% less risk for treatment failure, with a hazard ratio of 0.18 (95% confidence interval 0.04-0.73). Cumulative effects analysis revealed that the risk of TB increased significantly with the number of unfavorable genotypes in IL12 genes. Furthermore, MDR analysis showed potential higher-order gene-gene and gene-environment interactions and indicated different outcomes based on distinct genotype profiles. Results from this study demonstrate that genetic polymorphisms of the IL12-IFNG pathway may individually or jointly contribute to the susceptibility to and prognosis of pulmonary TB.
43: Fertility and sterility, 2010 Jun 11, 358(1-2)
Heparin inhibits interferon-gamma signaling in human endometrial stromal cells by interference with the cellular binding of interferon-gamma.
[Abstract]OBJECTIVE: To examine the impact of heparins on interferon-gamma (IFN-gamma) signaling in human endometrial stromal cells (ESCs) in vitro. DESIGN: In vitro experiment. SETTING: Research laboratory at a medical university center. PATIENT(S): Premenopausal women undergoing hysterectomy for benign reasons. INTERVENTION(S): The ESCs were isolated from hysterectomy specimens, decidualized in vitro using P and 17beta-E(2), and incubated with recombinant IFN-gamma, unfractionated heparin, and low molecular weight heparins (LMWHs). MAIN OUTCOME MEASURE(S): Interferon response factor 1 (IRF-1) and N-myc interactor (Nmi) messenger RNA (mRNA) were measured using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Phosphorylation of signal transducer and activator of transcription 1 (STAT-1) was detected by an in-cell Western assay, expression of the IFN-gamma receptor by flow cytometry. Cell-bound IFN-gamma was determined in lysates by an ELISA. RESULT(S): Heparin and LMWHs inhibit the IFN-gamma-mediated induction of IRF-1, but not Nmi in undifferentiated and decidualized ESCs. The phosphorylation of signal transducer and activator of transcription 1 STAT-1 upon IFN-gamma stimulation is inhibited as well. Heparin has no effect on the IFN-gamma receptor in ESCs, but inhibits the binding of IFN-gamma to the cells. CONCLUSION(S): Unfractionated heparin, as well as LMWHs, are able to inhibit IFN-gamma signaling in human ESCs and therefore might be clinically interesting agents to modulate the actions of this proinflammatory cytokine at the implantation site.
44: Research in veterinary science, 2010 Jun 9, 358(1-2)
Difference in the level of interferon gamma mRNA transcripts on stimulation of cattle and buffalo mononuclear cells with foot and mouth disease virus-antigen: A possible role of sequence variation in promoter region.
[Abstract]In an attempt to resolve the claim that buffaloes differ from cattle in disease progression, this study was undertaken to compare the mitogen (conA) or antigen (foot and mouth disease virus) induced expression levels of interferon gamma (IFN-gamma mRNA in peripheral blood mononuclear cells (PBMCs) by real-time quantitative PCR. In general, the levels of IFN-gamma mRNA were lower in buffaloes than in crossbred cattle. Significantly higher levels of IFN-gamma mRNA were also observed in crossbred cattle when induced with FMD virus (1mug). Analysis of the partial promoter sequences of the IFN-gamma gene from the respective species revealed a conserved 4 base (GTCT) deletion in all the buffalo promoter sequences. In-silico analysis indicated the binding of glucocorticoid receptor (GR) and erythroid nuclear factor (NF-E) to this region in cattle. GR has been shown to be a transcription factor by itself and also regulates other major transcription factors like NF-kappaB and AP-1. The differential expression levels of IFN-gamma mRNA between these species could be due to this deletion in the promoter region of buffalo. Further studies involving mobility shift and promoter assays would throw more light on the differential expression levels.
45: BMC infectious diseases, 2010 Jun 7, 10(1)
Analysis of eight genes modulating interferon gamma and human genetic susceptibility to tuberculosis: a case-control association study.
[Abstract]ABSTRACT: BACKGROUND: Interferon gamma is a major macrophage-activating cytokine during infection with Mycobacterium tuberculosis, the causative pathogen of tuberculosis, and its role has been well established in animal models and in humans. This cytokine is produced by activated T helper 1 cells, which can best deal with intracellular pathogens such as M.tuberculosis. Based on the hypothesis that genes which regulate interferon gamma may influence tuberculosis susceptibility, we investigated polymorphisms in eight candidate genes. METHODS: Fifty-four polymorphisms in eight candidate genes were genotyped in over 800 tuberculosis cases and healthy controls in a population-based case-control association study in a South African population. Genotyping methods used included the SNPlex Genotyping System, capillary electrophoresis of fluorescently labelled PCR products, TaqMan SNP genotyping assays or the amplification mutation refraction system. Single polymorphisms as well as haplotypes of the variants were tested for association with TB using statistical analyses. RESULTS: A haplotype in interleukin 12B was nominally associated with tuberculosis (p = 0.02), but after permutation testing, done to assess the significance for the entire analysis, this was not globally significant. In addition a novel allele was found for the interleukin 12B D5S2941 microsatellite. CONCLUSIONS: This study highlights the importance of using larger sample sizes when attempting validation of previously reported genetic associations. Initial studies may be false positives or may propose a stronger genetic effect than subsequently found to be the case.
46: Scandinavian journal of infectious diseases, 2010 May 31, 71(6)
Enzyme-linked immunospot assay for interferon-gamma to support the diagnosis of tuberculosis in diabetic patients.
[Abstract]Abstract The aim of this study was to evaluate the support to tuberculosis diagnosis of a new immunological tool, an enzyme-linked immunospot (ELISPOT) assay for interferon-gamma, in diabetic patients. From March 2007 to January 2008, diabetic patients with suspected pulmonary tuberculosis were enrolled in a tertiary care hospital. Data on clinical characteristics of the patients and conventional laboratory results were collected and blood samples were obtained for ELISPOT assay (T SPOT-TB; Oxford Immunotec Ltd, Oxford, UK). A total of 84 patients with suspected pulmonary tuberculosis were recruited. Fifty-one (60.7%) of these patients were considered to have pulmonary tuberculosis, including 42 (50%) with confirmed tuberculosis and 9 (10.7%) with probable tuberculosis. The overall (confirmed and probable tuberculosis) sensitivity, specificity, positive predictive value and negative predictive value of the ELISPOT assay were 84.3%, 66.7%, 79.6%, and 73.3%, respectively. The negative predictive value of the ELISPOT assay was significantly higher in patients with adequate glycaemic control (90% vs 56.3%). In conclusion, the ELISPOT assay can provide useful support in diagnosing pulmonary tuberculosis in diabetic patients, especially those with adequate glycaemic control.
47: The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010 Jun, 14 Suppl 1(3)
Proceedings of the second global symposium on interferon-gamma release assays.
[Abstract]BACKGROUND: Recent immigrants from developing countries (<2 years since immigration) are at very high risk of active TB disease due to reactivation of latent infections acquired in the country of origin. In industrialized low-incidence TB countries targeted testing programs for high risk groups could allow the detection of latently infected persons who would likely benefit from a course of preventive treatment. In this study we evaluated the tuberculin skin test (TST) and interferon-gamma enzyme-linked immunosorbent assay (QuantiFERON TB-gold in tube, QFT-IT) strategies for TB infection screening programs in recent immigrants from highly endemic countries. PATIENTS AND METHODS: This is a prospective cross-sectional study. Paired tests performed in 1,130 immigrants attending an outpatient ward, between 2005 and 2007 for any health problem were evaluated by intention-to-treat (ITT) and per-protocol (PP) analysis for efficiency and efficacy of screening program. RESULTS: Positive TST and QFT-IT were observed in 36.04 versus 29.82% (ITT) and in 45.27 versus 30.22% (PP) respectively. A higher drop-out rate was observed for TST (20.35 vs. 1.33%) (p < 0.0001). Second level assessment was accepted by half of the TST positive patients. Overall agreement rate between 887 paired tests was fair (k = 0.38). Higher k values were observed for higher TB prevalence rate in the country of origin (k = 0.43), for TST induration diameters >20 mM (k = 0.47), in subjects aged 40-50 years (k = 0.41) and in unvaccinated persons (k = 0.40). In a multiple logistic regression model continent of origin, class of TB prevalence in the country of origin and contacts with TB patients were found to be significantly associated with the probability of TST and QFT-IT positive result. Low education levels were associated only to an increased risk of TST positive results. CONCLUSIONS: The drawback of the TST screening strategy in recent immigrants from highly endemic countries is due to low sensitivity/specificity of the test and to high drop-out rate with an overall significant lowering in strategy efficacy/efficiency. The higher QFT-IT specificity prevents unnecessary overload of the health care system and, although more expensive, might represent a cost-effective alternative to TST in targeted screening programs directed to high risk populations.
48: Biology of reproduction, 2010 May 19, 215(6)
Murine Trophoblast Cells Induce NK Cell Interferon-Gamma Production Through KLRK1.
[Abstract]Murine models suggest that natural killer (NK) cells are important for normal implantation site development, in part, through the production of interferon gamma (IFNG). As KLRK1 (NKG2D) is expressed on human and murine uterine NK (uNK) cells, we examined the role of KLRK1 in the interaction between murine trophoblasts and NK cells. Flow cytometric analysis revealed murine trophoblast stem (TS) cells and differentiated trophoblast giant cells both expressed the KLRK1 ligand retinoic acid early transcript 1, or RAET1. Coculture of activated NK cells with either TS cells or giant cells led to the production of IFNG as measured by ELISA. In addition, coculture with TS cells led to the downregulation of KLRK1. Both responses were inhibited by soluble KLRK1 ligand but not by irrelevant protein. Further studies demonstrated the presence of KLRK1 ligand on uterine cells derived from either virgin or pregnant mice; though uterine RAET1 protein expression was upregulated in vitro by progesterone, but not estradiol. We suggest the interaction of KLRK1 and RAET1 may be involved in IFNG production by uNK cells, and thus this receptor-ligand pair may contribute to successful murine implantation site development.
49: Scandinavian journal of infectious diseases, 2010 May 20, 215(6)
Screening for latent tuberculosis infection in South Korean healthcare workers using a tuberculin skin test and whole blood interferon-gamma assay.
[Abstract]Abstract This study compared the results of a tuberculin skin test (TST) and a whole-blood interferon-gamma release assay (IGRA) to screen latent tuberculosis (TB) infection (LTBI) according to risk of TB exposure in South Korea. A cross-sectional comparison of 82 healthcare workers (HCWs) was performed from June 2009 to January 2010. Participants were grouped according to their risk for TB exposure: group 1, frequent and direct contact with active TB patients (n = 35); group 2, no known history of direct contact with active TB patients (n = 47). For the TST (10-mm induration cut-off), the positive response rate was 42.9% in group 1 and 34.0% in group 2 (p = 0.42). For the IGRA, the positive response rate was 40% in group 1 and 10.6% in group 2 (p = 0.002). Results obtained from the TST and the IGRA were not in significant agreement. The working duration of HCWs in TB-related departments was the only significant risk factor for LTBI (odds ratio 1.03; p = 0.031). Further, the IGRA can more accurately discriminate LTBI compared to the TST, based on the risk of TB exposure. These results suggest that the IGRA is diagnostically useful for LTBI in South Korean HCWs.
50: International journal of immunogenetics, 2010 Aug 1, 37(4)
Association of the +874 T/A interferon gamma polymorphism with infections in sickle cell disease.
[Abstract]Summary Infectious complications are a leading cause of morbidity and mortality in patients with sickle cell disease. Several mechanisms are supposed to contribute to this susceptibility. The exact reasons for the susceptibility of sickle cell patients to infection are not clear and are still a matter of debate. Interferon gamma (IFNgamma) is a key cytokine involved mainly in the defence against intracellular pathogens. We investigated a possible association of an IFNgamma +874 T/A polymorphism and infectious complications in sickle cell patients. Seventy-two sickle cell patients were typed for +874 T/A IFNgamma polymorphism. Genotype frequencies were different between cases and controls. Indeed, the T allele frequency was significantly higher in patients with infections than in patients without infections (P = 0.014). Our results suggest that the +874 T/A IFNgamma polymorphism is associated with infectious complications in sickle cell patients. T allele could be involved in infections in sickle cell patients.
51: Molecular medicine (Cambridge, Mass.), 2010 May, 16(5-6)
Interferon gamma-induced human guanylate binding protein 1 inhibits mammary tumor growth in mice.
[Abstract]Interferon gamma (IFN-gamma) has recently been implicated in cancer immunosurveillance. Among the most abundant proteins induced by IFN-gamma are guanylate binding proteins (GBPs), which belong to the superfamily of large GTPases and are widely expressed in various species. Here, we investigated whether the well-known human GBP-1 (hGBP-1), which has been shown to exert antiangiogenic activities and was described as a prognostic marker in colorectal carcinomas, may contribute to an IFN-gamma-mediated tumor defense. To this end, an IFN-independent, inducible hGBP-1 expression system was established in murine mammary carcinoma (TS/A) cells, which were then transplanted into syngeneic immune-competent Balb/c mice. Animals carrying TS/A cells that had been given doxycycline for induction of hGBP-1 expression revealed a significantly reduced tumor growth compared with mock-treated mice. Immunohistochemical analysis of the respective tumors demonstrated a tightly regulated, high-level expression of hGBP-1. No signs of an enhanced immunosurveillance were observed by investigating the number of infiltrating B and T cells. However, hemoglobin levels as well as the number of proliferating tumor cells were shown to be significantly reduced in hGBP-1-expressing tumors. This finding corresponded to reduced amounts of vascular endothelial growth factor A (VEGF-A) released by hGBP-1-expressing TS/A cells in vitro and reduced VEGF-A protein levels in the corresponding mammary tumors in vivo. The results suggest that hGBP-1 may contribute to IFN-gamma-mediated antitumorigenic activities by inhibiting paracrine effects of tumor cells on angiogenesis. Consequently, owing to these activities GBPs might be considered as potent members in an innate, IFN-gamma-induced antitumoral defense system.
52: American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics, 2010 May, 137(5)
In-vitro study of cellular viability and nitric oxide production by J774 macrophages stimulated by interferon gamma with ceramic, polycarbonate, and polyoxymethylene brackets.
[Abstract]INTRODUCTION: Ceramic brackets are chemically inert in the oral cavity, whereas polycarbonate and polyoxymethylene brackets can degrade and release bisphenol-A and formaldehyde, respectively. More reliable tests are needed to assess the potential toxicity of these materials. In addition to traditional cytotoxicity tests, the study of nitric oxide (NO) cellular production stimulated by a specific material has been shown to be a reliable tool for evaluating cytotoxic potential. The purpose of this study was to assess, with esthetic brackets, cellular viability by 3,(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide assay (Sigma, St. Louis, Mo) in the macrophage cell line J774 stimulated with interferon gamma. Interferon gamma is a key cytokine in the activation of macrophages, plays an important role in immunologic processes, and also quantifies NO production by these macrophages. METHODS: Well plates were seeded with 2 x 104 J774 cells per well, in a volume of 100 microL, resuspended in Roswell Park Memorial Institute Supplemented Medium 1640. The macrophage cell line J774 was stimulated with interferon gamma. Ceramic, polycarbonate, and polyoxymethylene brackets were added and kept in the culture for 24, 48, or 72 hours in 5% carbon dioxide at 37 degrees C; the control samples did not include brackets. At the end of each incubation period, the supernatant was collected for posterior NO quantification, and the cells were evaluated for cytotoxicity. RESULTS: Cellular viability in all groups was higher at 72 hours than at 24 hours. The final means in the bracket groups did not show significant differences compared with the control group. NO production was significantly greater in all groups at the final time than at the initial time. However, the brackets with the interferon gamma stimulation did not result in greater NO production than did the cells in the control group.
53: The Journal of antibiotics, 2010 May 7, 135(1-2)
Lactariolines A and B: new guaiane sesquiterpenes with a modulatory effect on interferon-gamma production from the fruiting bodies of Lactarius hatsudake.
[Abstract]Recombinant equine interferon-gamma (reIFN-gamma) was prepared using a baculovirus expression system and its antiviral activity was investigated using several equine viruses. The reIFN-gamma suppressed the replication of all equine viruses used in the present experiment in horse cell cultures, but did not affect the growth of host cells at concentrations of less than 1000 u/ml. A strong antiviral effect was observed, especially against RNA viruses. Equine picornavirus, equine rhinovirus and equine arteritis virus could not be propagated at all in 100 u/ml reIFN-gamma when 100 TCID(50) of infective viruses was inoculated to cultivated horse cells. DNA viruses, equine herpesvirus types 1, 2, 3 and 4 and equine adenovirus, were less sensitive to reIFN-gamma but their growth became less than 1/100 in the cells treated with 100 u/ml reIFN-gamma compared to untreated cells. The antiviral effects were decreased in the cells of heterologous species and more than 1000 u/ml reIFN-gamma was required to induce an antiviral effect.
54: Clinical and vaccine immunology : CVI, 2010 May 5, 135(1-2)
Disseminated penicilliosis, recurrent bacteremic non-typhoidal salmonellosis and burkholderiosis associated with acquired immunodeficiency due to autoantibody against interferon gamma.
[Abstract]Acquired immunodeficiency due to autoantibody against interferon gamma has recently been associated with opportunistic non-tuberculous mycobacteriosis especially among Southeast Asians. We report another 8 cases, all except one being apparently immunocompetent hosts, who suffered from concomitant or sequential infections by other intracellular pathogens causing penicilliosis, extra-intestinal non-typhoidal salmonellosis and burkholderiosis. The only case with an underlying immunodeficiency syndrome had systemic lupus erythematosus which was quiescent throughout the multiple infective episodes. Eight out of 10 (80.0%) patients with serological evidence of penicilliosis, 5 out of 7 (71.4%) with culture-positive extra-intestinal non-typhoidal salmonellosis, 5 out of 28 with serological evidence of melioidosis (17.9%) and 7 out of 13 with culture-positive non-tuberculous mycobacteriosis (53.8%) possessed autoantibody against interferon gamma, whereas only 1 out of 100 patients with systemic lupus erythematosus did. Our study represents the first and largest case series linking this emerging immunodeficiency syndrome with these atypical infections in apparently immunocompetent hosts. Thus, we advocate that any patient with unexplained recurrent or polymicrobial infections due to these intracellular pathogens should be screened for acquired immunodeficiency due to autoantibody against interferon gamma.
55: PloS one, 2010, 5(4)
Feasibility and diagnostic utility of antigen-specific interferon-gamma responses for rapid immunodiagnosis of tuberculosis using induced sputum.
[Abstract]BACKGROUND: The diagnosis of smear-negative or sputum-scarce tuberculosis (TB) is problematic as culture takes several weeks and representative biological samples are difficult to obtain. RD-1 antigen-specific interferon-gamma release assays (IGRAs) are sensitive and specific blood-based tests for the diagnosis of M. tuberculosis infection. The feasibility and diagnostic utility of this rapid immunodiagnostic assay, using cells from induced sputum, is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Cells isolated from induced sputum were co-cultured with ESAT-6 and CFP-10 antigens using a standardized enzyme-linked immunospot (ELISPOT) assay (T-SPOT.TB) in 101 consecutively recruited TB suspects or non-TB controls. An optimization phase using 28 samples was followed by a validation phase using samples from 73 participants (20 with definite or probable TB, and 48 with non-TB). Despite optimization of sputum processing 65/73 (89%) of the IGRAs in the validation phase were inconclusive. 44/73 (60%) tests failed due to sputum induction-related factors [sputum induction-related adverse events (n = 5), inadequate sputum volume (n = 8), non-homogenisable sputum (n = 7), and insufficient numbers of cells to perform the assay (n = 24)], whilst 20/73 (27%) tests failed due T-SPOT.TB assay-related factors [excessive debris precluding reading of spots in the ELISPOT well (n = 6), failure of the positive control (n = 11), or high spot count in the negative control (n = 3)]. Only 8/73 (11%) of the available samples could therefore be correctly categorized (7 definite or probable TB, and 1 non-TB patient). Thus, 13/20 (65%) of the definite or probable TB cases remained undiagnosed. CONCLUSIONS/SIGNIFICANCE: Rapid immunodiagnosis of pulmonary TB by antigen-specific IFN-gamma ELISPOT responses, using cells from induced sputum, is possible. However, the test, in its current ELISPOT format, is not clinically useful because the majority of the assays are inconclusive.
56: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology, 2010 May, 35(5)
Indeterminate results of a tuberculosis-specific interferon-gamma release assay in immunocompromised patients.
[Abstract]Microglial cells play an important role in the inflammatory response of a broad range of brain diseases including stroke, brain infection and neurodegenerative diseases. However, there is very little information regarding how to protect microglial cells. Here, we showed that incubation of the C8-B4 mouse microglial cells with lipopolysaccharide (LPS) plus interferon-gamma (IFN gamma) induced cytotoxicity as assessed by the amount of lactate dehydrogenase (LDH) released from the cells. Preconditioning the cells with morphine for 30 min concentration-dependently reduced LPS plus IFN gamma-induced cell injury. This morphine preconditioning effect was abolished by naloxone, a general opioid receptor antagonist, by naltrindole, a selective delta opioid receptor antagonist and by 7-benzylidenenaltrexone maleate, a selective delta(1) opioid receptor antagonist. However, this protective effect was not affected by beta-funaltrexamine, a selective mu opioid receptor antagonist, nor-binaltorphimine, a selective kappa opioid receptor antagonist or naltriben, a selective delta(2) opioid receptor antagonist. LPS plus IFN gamma induced the expression of inducible nitric oxide synthase (iNOS), which was not affected by morphine preconditioning. Our results suggest that morphine induced a preconditioning effect in microglial cells. This effect may be mediated by delta 1 opioid receptors and may not be through inhibiting the expression of iNOS, a potentially harmful protein.
57: The international journal of biochemistry & cell biology, 2010 Apr 29, 48(3)
Induction of indoleamine 2,3-dioxygenase by interferon-gamma in human lens epithelial cells: Apoptosis through the formation of 3-hydroxykynurenine.
[Abstract]Interferon-gamma (IFN-gamma) is known to cause apoptosis of lens epithelial cells and cataract formation, but the molecular mechanisms underlying these effects are unknown. IFN-gamma induces the expression of indoleamine 2,3-dioxygenase (IDO) and thereby enhances the production of kynurenines from L-tryptophan. The present study was designed to investigate the role of IDO and kynurenines in the IFN-gamma-mediated apoptosis of lens epithelial cells and to determine the signaling pathways involved. IFN-gamma stimulated the synthesis of IDO and activated the JAK-STAT1 signaling pathway in human lens epithelial cells (HLE-B3) in a dose-dependent manner. Meanwhile, fludarabine, an inhibitor of STAT1 activation, blocked IFN-gamma-mediated IDO expression. N-formylkynurenine, kynurenine (Kyn) and 3-hydroxykynurenine (3OHKyn) were detected in cells, with 3OHKyn concentrations being higher than those of the other kynurenines. The intracellular production of kynurenines was completely blocked by 1-methyl-DL-tryptophan (MT), an inhibitor of IDO. Kyn- and 3OHKyn-modified proteins were detected in IFN-gamma-treated cells. The induction of IDO by IFN-gamma in HLE-B3 cells caused increases in intracellular ROS, cytosolic cytochrome c and caspase-3 activity, along with a decrease in protein-free thiol content. These changes were accompanied by apoptosis. At equimolar concentrations, 3OHKyn caused higher levels of apoptosis than the other kynurenines in HLE-B3 cells. MT and a kynurenine 3-hydroxylase inhibitor (Ro61-8048) effectively inhibited IFN-gamma-mediated apoptosis in HLE-B3 cells. Our results show that the induction of IDO by IFN-gamma is JAK-STAT1 pathway-dependent and that this induction causes 3OHKyn-mediated apoptosis in HLE-B3 cells. These data suggest that IDO-mediated kynurenine formation could play a role in cataract formation related to chronic inflammation.
58: The Journal of infection, 2010 Apr 29, 48(3)
Serial Testing of Interferon-gamma-release Assays for the Diagnosis of Latent Tuberculosis in Hemodialysis Patients.
[Abstract]INTRODUCTION: The performance of serial interferon-gamma-release assays (IGRAs) for the diagnosis of latent tuberculosis has not been studied in hemodialysis patients. METHOD: The QuantiFERON-TB-Gold In-Tube test (QFT) and T-SPOT-TB test (TSPOT) were performed one year after initial testing at a hemodialysis center. RESULTS: Ninety-eight patients were included in the final analysis. Positive rates for the initial tuberculin skin test (TST), QFT and TSPOT were 26.5%, 43.9% and 58.2%, respectively. The follow-up QFT and TSPOT showed positive responses in 52.0% and 53.1%. Conversion rates of the QFT and TSPOT were 20.0% and 26.8%. Reversion rates of the QFT and TSPOT were 16.3% and 29.8%; however, they decreased to 0.0% and 4.8% in patients with a concordantly positive response at the initial TST. A group at high risk for latent tuberculosis increased the risk for the TSPOT conversion (odds ratio [95% confidence interval], 7.76 [1.27-47.40]) and showed a trend of increasing the risk for the QFT conversion (1.97 [0.45-8.71]). Reversion of both the QFT (18.92 [2.01-178.65]) and TSPOT (6.16 [1.57-24.19]) occurred more frequently in the group at low risk. CONCLUSIONS: Both conversion and reversion of the IGRAs were associated with the risk for latent tuberculosis in hemodialysis patients. However, serial IGRAs results should be interpreted cautiously due to their high variability.
59: Vaccine, 2010 Apr 27, 48(3)
OprF/I-vaccinated sera inhibit binding of human interferon-gamma to Pseudomonas aeruginosa.
[Abstract]The recombinant outer membrane protein OprF/I has been demonstrated in previous studies to protect against Pseudomonas aeruginosa infection through a mechanism of enhanced antibody-mediated opsonophagocytosis. Recent evidence indicates that P. aeruginosa enhances its virulence phenotype as a consequence of binding to human IFN-gamma through an outer membrane protein, OprF. In this study, we demonstrate that a single boost injection of OprF/I vaccine elicited a strong OprF/I-specific antibody response in individuals who were previously vaccinated with OprF/I in a clinical trial. The OprF/I-vaccinated sera inhibit P. aeruginosa binding to IFN-gamma, suggesting an alternative mechanism by which the OprF/I vaccine confers protection against P. aeruginosa infection.
60: Molecular and cellular biochemistry, 2010 Apr 28, 48(3)
Novel 1-alkyl-tryptophan derivatives downregulate IDO1 and IDO2 mRNA expression induced by interferon-gamma in dendritic cells.
[Abstract]Indoleamine 2,3-dioxygenase (IDO) is an enzyme that suppresses adaptive T-cell immunity by catabolizing tryptophan from the cellular microenvironment. Inhibition of IDO pathway might enhance the efficacy of immunotherapeutic strategies for cancer. We synthesized 1-alkyl-tryptophan targeted IDO inhibitors and compared their effects on IDO expression and activity in dendritic cells (DCs) with the common IDO inhibitor 1-methyl-DL: -tryptophan (1-MT). The IDO gene expression was examined by RT-PCR and realtime PCR. The toxicity of these analogs on the proliferation of DCs was detected by MTT assay. All of these analogs inhibited IDO expression and activity induced by IFN-gamma and showed no cytotoxicity to DCs at 100 muM. 1-MT intensively suppressed IDO1 expression and activity in DCs, and 1-propyl-tryptophan (1-PT) and 1-isopropyl-tryptophan (1-isoPT) moderately inhibited them. 1-Butyl-tryptophan (1-BT) and 1-ethyl-tryptophan (1-ET) mainly inhibited IDO2 expression. Our results suggest that those analogs differed in their inhibitory activity on IDO expression may give us a clue for developing active IDO inhibitors.
61: Lung, 2010 Apr 27, 48(3)
Comparison of T-Cell Interferon-gamma Release Assays for Mycobacterium tuberculosis-Specific Antigens in Patients with Active and Latent Tuberculosis.
[Abstract]Through the use of QuantiFERON-TB Gold, a commercial IFN-gamma assay, we compared differences in quantitative T-cell responses to Mycobacterium tuberculosis (MTB)-specific antigens [QuantiFERON TB-2G (QFT-2G)] between patients with active tuberculosis (TB) disease and those with latent TB infection (LTBI). The patient group consisted of 180 patients with active TB disease (culture-positive for MTB) and 50 screening contacts with LTBI-positive response to the QFT-2G test. We prospectively performed a tuberculin skin test (TST) and a QFT-2G test for all subjects. The median IFN-gamma levels upon the application of both antigens, ESAT-6 and CFP-10, were significantly higher in patients with active TB disease than in those with LTBI. A combined positive response to both antigens occurred at a higher rate in patients with active TB disease than in those with LTBI. There were no significant relationships between the quantitative responses of IFN-gamma to both antigens and the maximum induration on TST in both patient groups. We demonstrated significant differences in the quantitative responses of IFN-gamma to MTB between patients with active TB disease and those with LTBI in this study. However, there was an overlap in the IFN-gamma levels between active TB disease and LTBI groups. Therefore, it would be difficult to use the QFT-2G test to completely discriminate active TB disease from LTBI.
62: Infection, 2010 Apr 22, 48(3)
Interferon-gamma releasing assay versus tuberculin skin testing for latent tuberculosis infection in targeted screening programs for high risk immigrants.
[Abstract]BACKGROUND: Recent immigrants from developing countries (<2 years since immigration) are at very high risk of active TB disease due to reactivation of latent infections acquired in the country of origin. In industrialized low-incidence TB countries targeted testing programs for high risk groups could allow the detection of latently infected persons who would likely benefit from a course of preventive treatment. In this study we evaluated the tuberculin skin test (TST) and interferon-gamma enzyme-linked immunosorbent assay (QuantiFERON TB-gold in tube, QFT-IT) strategies for TB infection screening programs in recent immigrants from highly endemic countries. PATIENTS AND METHODS: This is a prospective cross-sectional study. Paired tests performed in 1,130 immigrants attending an outpatient ward, between 2005 and 2007 for any health problem were evaluated by intention-to-treat (ITT) and per-protocol (PP) analysis for efficiency and efficacy of screening program. RESULTS: Positive TST and QFT-IT were observed in 36.04 versus 29.82% (ITT) and in 45.27 versus 30.22% (PP) respectively. A higher drop-out rate was observed for TST (20.35 vs. 1.33%) (p < 0.0001). Second level assessment was accepted by half of the TST positive patients. Overall agreement rate between 887 paired tests was fair (k = 0.38). Higher k values were observed for higher TB prevalence rate in the country of origin (k = 0.43), for TST induration diameters >20 mM (k = 0.47), in subjects aged 40-50 years (k = 0.41) and in unvaccinated persons (k = 0.40). In a multiple logistic regression model continent of origin, class of TB prevalence in the country of origin and contacts with TB patients were found to be significantly associated with the probability of TST and QFT-IT positive result. Low education levels were associated only to an increased risk of TST positive results. CONCLUSIONS: The drawback of the TST screening strategy in recent immigrants from highly endemic countries is due to low sensitivity/specificity of the test and to high drop-out rate with an overall significant lowering in strategy efficacy/efficiency. The higher QFT-IT specificity prevents unnecessary overload of the health care system and, although more expensive, might represent a cost-effective alternative to TST in targeted screening programs directed to high risk populations.
63: Immunity, 2010 Apr 14, 355(1-2)
The Transcription Factor GATA3 Actively Represses RUNX3 Protein-Regulated Production of Interferon-gamma.
[Abstract]The transcription factor GATA3 is crucial for the differentiation of naive CD4(+) T cells into T helper 2 (Th2) cells. Here, we show that deletion of Gata3 allowed the appearance of interferon-gamma (IFN-gamma)-producing cells in the absence of interleukin-12 (IL-12) and IFN-gamma. Such IFN-gamma production was transcription factor T-bet independent. Another T-box-containing transcription factor Eomes, but not T-bet, was induced both in GATA3-deficient CD4(+) T cells differentiated under Th2 cell conditions and in Th2 cells with enforced Runx3 expression, contributing to IFN-gamma production. GATA3 overexpression blocked Runx3-mediated Eomes induction and IFN-gamma production, and GATA3 protein physically interacted with Runx3 protein. Furthermore, we found that Runx3 directly bound to multiple regulatory elements of the Ifng gene and that blocking Runx3 function in either Th1 or GATA3-deficient "Th2" cells results in diminished IFN-gamma production by these cells. Thus, the Runx3-mediated pathway, actively suppressed by GATA3, induces IFN-gamma production in a STAT4- and T-bet-independent manner.
64: The international journal of biochemistry & cell biology, 2010 Apr 12, 355(1-2)
Knockdown of hTERT and concurrent treatment with interferon-gamma inhibited proliferation and invasion of human glioblastoma cell lines.
[Abstract]Human telomerase reverse transcriptase (hTERT) is the catalytic component of telomerase that facilitates tumor cell invasion and proliferation. Telomerase and hTERT are remarkably upregulated in majority of cancers including glioblastoma. Interferon-gamma (IFN-gamma) modulates several cellular activities including cell cycle and multiplication through transcriptional regulation. The present investigation was designed to unravel the molecular mechanisms of the inhibition of cell proliferation, migration, and invasion of human glioblastoma SNB-19 and LN-18 cell lines after knockdown of hTERT using a plasmid vector based siRNA and concurrent treatment with IFN-gamma. We observed more than 80% inhibition of cell proliferation, migration, and invasion of both cell lines after the treatment with combination of hTERT siRNA and IFN-gamma. Our studies also showed accumulation of apoptotic cells in subG1 phase and an increase in cell population in G0/G1 with a reduction in G2/M phase indicating cell cycle arrest in G0/G1 phase for apoptosis. Semiquantitative and real-time RT-PCR analyses demonstrated significant downregulation of c-Myc and upregulation of p21 Waf1 and p27 Kip1. Western blotting confirmed the downregulation of the molecules involved in cell proliferation, migration, and invasion and also showed upregulation of cell cycle inhibitors. In conclusion, our study demonstrated that knockdown of hTERT siRNA and concurrent treatment with IFN-gamma effectively inhibited cell proliferation, migration, and invasion in glioblastoma cells through downregulation of the molecules involved in these processes and cell cycle inhibition. Therefore, the combination of hTERT siRNA and IFN-gamma offers a potential therapeutic strategy for controlling growth of human glioblastoma cells.
65: The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010 May, 14(5)
Interferon-gamma release assay clarifies the effect of bacille Calmette-Gu¨¦rin vaccination in Greek army recruits.
[Abstract]OBJECTIVE: To compare the most recent commercial interferon-gamma release assay (IGRA), the QuantiFERON-TB Gold In-Tube (QFT-GIT), with the tuberculin skin test (TST) in Greek army recruits who were bacille Calmette-Gu¨¦rin (BCG) vaccinated during childhood and had no history of tuberculosis (TB) exposure. METHOD: We conducted a cross-sectional comparison study of 1750 young army recruits. TST was performed on all participants, while QFT-GIT was performed in all subjects with TST > 0 mm and in 18 TST-negative controls (TST = 0 mm). RESULTS: Among the study subjects, 5.4% (96/1750) had TST indurations of >or=10 mm, and 3.4% (59/1750) had indurations of >or=15 mm. Among subjects with a positive TST, 11.4% (11/96) tested positive on QFT-GIT. All those with QFT-GIT positivity had TST indurations of >or=15 mm, and none of those with TST indurations of 10-14 mm were positive by QFT-GIT. The overall agreement between TST and QFT-GIT was poor (kappa = 0.02). CONCLUSION: We found a significant discordance between TST and QFT-GIT in BCG-vaccinated Greek army recruits consistent with previous studies showing that BCG received after infancy produces false-positive TST reactions. Our findings underline the need for a two-step approach in diagnosing latent TB infection in all BCG-vaccinated individuals: initial TST screening, followed by an IGRA to confirm TST positivity.
66: Journal of immunological methods, 2010 Apr 8, 41(4)
Isolation of scFv fragments specific for monokine induced by interferon-gamma (MIG) using phage display.
[Abstract]Iterative affinity selection procedures were used to isolate a number of single chain Fv (scFv) antibody fragment clones from na?ve Tomlinson I+J phage display libraries that specifically recognize and bind a chemokine, monokine induced by interferon-gamma (MIG/CXCL9). MIG is an important transplant rejection/biology chemokine protein. ELISA-based affinity characterization results indicate that selectants preferentially bind to MIG in the presence of key biopanning component materials and closely related chemokine proteins. These novel antibody fragments may find utility as molecular affinity interface receptors in various electrochemical biosensor platforms to provide specific MIG binding capability with potential applications in transplant rejection monitoring, and other biomedical applications where detection of MIG level is important.
67: American journal of physiology. Gastrointestinal and liver physiology, 2010 Apr 8, 41(4)
Fasting-Induced Intestinal Apoptosis is Mediated by Inducible Nitric Oxide Synthase and Interferon-{gamma} in Rat.
[Abstract]Nitric oxide (NO) is associated with intestinal apoptosis in health and disease. This study aimed to investigate the role of intestinal NO in the regulation of apoptosis during fasting in rats. Male Wistar rats were divided into two groups and subcutaneously injected with saline (SA) or aminoguanidine (AG), followed by fasting for 24, 48, 60 and 72 h. At each time point, the jejunum was subjected to histological evaluation for enterocyte apoptosis using histomorphometric assessment and TUNEL analysis. We performed immunohistochemistry for inducible NO synthase (iNOS) expression in the jejunum and measured tissue nitrite levels using HPLC and 8-hydroxydeoxyguanosine adduct using ELISA, indicative of endogenous NO production and reactive oxygen species (ROS) production, respectively. Jejunal transcriptional levels of iNOS, neuronal NO synthase (nNOS) and interferon-gamma (IFN-gamma) were also determined using RT-PCR. Fasting caused significant jejunal mucosal atrophy due to increased apoptosis, and attenuated cell proliferation with increased iNOS transcription, its protein expression in intestinal epithelial cells (IEC), and jejunal nitrite levels. However, AG treatment histologically reduced apoptosis with inhibition of fasting-induced iNOS transcription, protein expression, and nitrite production. We also observed fasting-induced ROS production and subsequent IFN-gamma transcription, which were all inhibited by AG treatment. Furthermore, we observed reduced transcriptional levels of nNOS, known to suppress iNOS activation physiologically. These results suggest that fasting-induced iNOS activation in IEC may induce apoptosis mediators such as IFN-gamma via a ROS-mediated mechanism, and also a possible role of nNOS in the regulation of iNOS activity in fasting-induced apoptosis.
68: Clinical and vaccine immunology : CVI, 2010 Apr 7, 41(4)
Kinetics of a tuberculosis-specific interferon-gamma release assay in military personnel with a positive tuberculin skin test.
[Abstract]Treatment of latent tuberculosis infection based on the tuberculin skin test (TST) is inaccurate due to false-positive TST results after BCG vaccination or exposure to nontuberculous mycobacteria (NTM). Interferon-gamma release assays (IGRAs) are based on M. tuberculosis-specific antigens. In a previous study among BCG-na?ve military employees, a positive TST after deployment was mostly associated with a negative IGRA result, suggesting NTM exposure. Data regarding kinetics of IGRAs are limited and controversial. This study aimed to re-assess the rate of false positive TST results and to evaluate the kinetics of QuantiferonTB Gold In-Tube (QFT-Git) in military personnel with a positive TST. QFT-Git was performed at inclusion and repeated after 2, 6, 12 and 18 or 24 months. Of 192 participants, 17 were recruits and 175 were screened after deployment (N=169) or because of travel or health care work. Baseline positive QFT-Git results were observed in 7/17 (41.2%) and 12/174 (6.9%), respectively. During follow-up, a negative QFT-Git result remained negative in 163/165 (98.8%) participants. Of 18 subjects with initial positive QFT-Git, reversion to negative occurred in 1/6 (16%) recruits, compared with 8/12 (66%) subjects after deployment/other risk factors (p=0.046). The quantitive result was significantly lower in subjects with reversion compared to those with consistent positive results (p=0.017). This study confirmed a low rate of positive QFT-Git results among military personnel with a positive TST after deployment, supporting the hypothesis of NTM exposure. Reversion of the majority of initially low positive QFT-Git results indicates that QFT-Git may be useful to diagnose later reinfection.
69: Molecular therapy : the journal of the American Society of Gene Therapy, 2010 Apr 6, 41(4)
Phase II Clinical Trial of Intratumoral Application of TG1042 (Adenovirus-interferon-gamma) in Patients With Advanced Cutaneous T-cell Lymphomas and Multilesional Cutaneous B-cell Lymphomas.
[Abstract]Cutaneous lymphomas (CLs) are a heterogeneous group of lymphoproliferative disorders that are manageable by immunotherapy. Twenty-one patients were enrolled in a prospective open-label, dose-escalation multicenter study evaluating the effects of repeated TG1042 [adenovirus-interferon (IFN)-gamma] intralesional injections in patients with primary CLs, of which 18 were of T-cell and 3 of B-cell type. Repeated intralesional therapy using TG1042 consistently results in local tumor regressions in about half of treated patients and one-third of patients also in regressions in noninjected distant lesions, likely reflecting the systemic immune activation after intralesional therapy. Treatment was well tolerated with few adverse events including injection site reactions, chills, lymphopenia, and fever. Immune monitoring in the peripheral blood demonstrated systemic immune activation and the induction of antibodies against tumor antigens in some patients without clear association with clinical responses. CLs, in particular B-cell lymphomas with high objective response rates, seem to be excellent targets for this type of immunotherapy.
70: Protein expression and purification, 2010 Apr 1, 22(3)
Purification and refolding of recombinant human interferon-gamma in urea-ammonium chloride solution.
[Abstract]A method for purification and refolding of recombinant human interferon-gamma (hIFNgamma) from inclusion bodies is described. It includes the following steps: i) solubilization of inclusion bodies in 7.4 M guanidinium hydrochloride; ii) purification of the denatured hIFNgamma by hydrophobic chromatography on Octyl-Sepharose column (one step elution with 6 M urea/1 M ammonium chloride); iii) refolding of the partly purified protein in 0.75 M urea, 20 mM Tris-HCl, pH 8.2; iv) purification of the refolded protein by CM-Sepharose chromatography. The protein thus obtained is characterized by the following general parameters: yield 1.0 mg/g wet cell mass; purity > 99 %; specific activity 2x10(8) IU/mg; stability - more than two years as a lyophilized powder and more than two months in solution at 4 (o)C.
71: Human immunology, 2010 Mar 27, 30(6)
IFNG +874T/A Polymorphism and Cytokine Plasma Levels are Associated with Susceptibility to Mycobacterium tuberculosis Infection and Clinical Manifestation of Tuberculosis.
[Abstract]Regarding the importance of interferon-gamma (IFN-gamma) in protective immunity against Mycobacterium tuberculosis and the functional role of IFNG +874T/A single nucleotide polymorphism (SNP) in the IFN-gamma production, in the present study it was investigated the relationship of this genetic polymorphism with susceptibility to tuberculosis (TB). One hundred and twenty-nine subjects with pulmonary tuberculosis (PTB), 33 with extrapulmonary tuberculosis (EPTB), and 156 control individuals were investigated. Blood samples were drawn and plasma was used to measure IFN-gamma serum concentration by enzyme-linked immunoassay. DNA samples were extracted from leucocytes and used to investigate +874T/A polymorphism in IFNG gene using ASO-PCR (allele specific oligonucleotide - polymerase chain reaction). An association between the presence of the allele +874A and the genotype +874AA with the active tuberculosis was found (p<0.0001, CI = 95%, 1.64 - 3.22), at the same time that allele + 874T and genotype +874T/T were more frequent in the control group. The average plasma concentration of IFN-gamma among patients with tuberculosis was significantly lower than in the control group, and lower in the EPTB group than in the group with PTB, suggesting a relationship of low plasma levels of this cytokine with active tuberculosis and the progression to more serious forms of the disease. Furthermore, we observed the association of the +874T/T and +874A/A genotypes with high and low IFN-gamma plasma concentrations, respectively, both in TB patients and control groups. Thus, our findings suggest association of the IFNG +874T/A polymorphism with the susceptibility to M. tuberculosis infection in the studied population.
72: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2010 Mar 26, 30(6)
Exogenous Interferon-gamma Immunotherapy for Invasive Fungal Infections in Kidney Transplant Patients.
[Abstract]The incidence of invasive fungal infections (IFIs) in nonneutropenic solid organ transplant patients is increasing. We report our clinical experience with the use of interferon-gamma (IFN-gamma) immunotherapy in seven renal transplant patients who developed life threatening, disseminated IFIs refractory to conventional antifungal drug therapy. The infections were all microbiologically and histologically proven. The rapid cure of these disseminated infections with exogenous IFN-gamma injections was not associated with impaired kidney allograft function despite the use of liposomal amphotericin B in all cases. No clinical toxicity from the IFN-gamma immunotherapy was seen and no IFI relapsed during long-term follow-up. Our experience is both uncontrolled and in patients with unpredictable fungal infection-related outcomes. However, compared to standard approaches, the accelerated cure of life threatening, disseminated IFIs with 6 weeks of combination antifungal drug therapy and IFN-gamma immunotherapy saved lives, retained allograft function and led to substantial cost savings in this small patient group.
73: International journal of cancer. Journal international du cancer, 2010 Mar 23, 30(6)
Tumor rejection by local interferon gamma induction in established tumors is associated with blood vessel destruction and necrosis.
[Abstract]It has been shown that injecting a suspension of IFN-gamma-secreting tumor cells results in their rejection. This effect has been attributed to IFN-gamma preventing tumor stroma formation but not to a direct effect on the cancer cells. However, it is not known, which influence IFN-gamma has on tumors with an established stroma. To address this question, the plasmacytoma cell line J558L was transduced with a vector allowing doxycycline-inducible IFN-gamma gene expression. After the injection of the tumor cells into mice, IFN-gamma was induced at different time points. Tumors did not grow when inducing IFN-gamma immediately after tumor cell inoculation, while approximately half of the tumors were rejected when IFN-gamma was induced in early established tumors within 2 weeks. Induction of IFN-gamma 2-3 weeks after tumor cell inoculation was less efficient (0-17% rejection). IFN-gamma induction in established tumors led to a reduction of CD146(+) endothelial cells and massive necrosis. Together, we show that vascularized tumors can be rejected by local IFN-gamma expression, but that rejection of established tumors was less efficient over time. This suggests that transplanted tumors became less susceptible to local IFN-gamma treatment the better they are established. (c) 2010 UICC.
74: Tissue antigens, 2010 Mar 14, 10(1)
Interleukin-18 and interferon-gamma polymorphisms in Brazilian human immunodeficiency virus-1-infected patients presenting with lipodystrophy syndrome.
[Abstract]Cytokines play important roles in the pathogenesis of lipodystrophy syndrome (LS). Single nucleotide polymorphisms (SNPs) at positions -607(C/A) and -137(C/G) in the promoter region of the interleukin-18 (IL-18) gene and at position +874(T/A) of the interferon-gamma (IFN-gamma) gene are related to the expression of these cytokines. To examine whether IL-18 and IFN-gamma polymorphisms are associated with LS, these SNPs were genotyped in 88 human immunodeficiency virus (HIV)-infected patients presenting LS, 79 HIV-infected without LS, and 133 healthy controls. The -607A allele, -607AA genotype, and -137G/-607A and -137C/-607A haplotypes in the IL-18 gene were over-represented in HIV patients presenting LS. The -137G/-607C haplotype was associated with protection against LS. These results indicate that the -607(C/A) SNP is associated with LS development in HIV-infected patients.
75: European journal of gastroenterology & hepatology, 2010 Apr, 22(4)
Synergistic antifibrotic effect of verapamil and interferon-gamma in rats: partially based on enhanced verapamil oral bioavailability.
[Abstract]OBJECTIVE: The objective of this study was to investigate the synergistic antifibrotic effect of verapamil and interferon-gamma (IFN-gamma) on rat liver fibrosis and its potential pharmacokinetic-based mechanism. METHODS: Rat liver fibrosis model was successfully established, and both the therapeutic effects and pharmacokinetic parameters of verapamil were evaluated after the administration of verapamil with or without IFN-gamma. The activities of cytochrome P450 3A (CYP3A) and the expression of multidrug resistance (Mdr) mRNA were measured in liver and small intestine. RESULTS: The results showed the synergistic antifibrotic effect of verapamil and IFN-gamma in rat liver fibrosis, in terms of decreased serum L-alanine aminotransferase activity and liver hydroxyproline content and improved liver histopathology, when compared with rats treated with verapamil or IFN-gamma alone. Meanwhile, the area under the curve of verapamil increased significantly after single administration of verapamil and IFN-gamma and the concentration of verapamil in plasma increased, but the metabolite : parent ratio of verapamil decreased after consecutive administrations of verapamil and IFN-gamma. Furthermore, the activities of CYP3A in both the liver and the small intestine and the expression of Mdr in small intestine decreased in rats treated with verapamil and IFN-gamma. CONCLUSION: All these results indicated that the combination of verapamil and IFN-gamma exerts a synergistic antifibrotic effect on rat liver fibrosis. The mechanism was partially based on the enhanced oral bioavailability of verapamil by increasing the intestinal absorption as well as reducing the first-pass metabolism, through inhibition of CYP3A activity and P-glycoprotein expression by IFN-gamma
76: Journal of immunology (Baltimore, Md. : 1950), 2010 Mar 19, 10(1)
Activating Transcription Factor 3 Is a Positive Regulator of Human IFNG Gene Expression.
[Abstract]IL-12 and IL-18 are essential for Th1 differentiation, whereas the role of IFN-alpha in Th1 development is less understood. In this microarray-based study, we searched for genes that are regulated by IFN-alpha, IL-12, or the combination of IL-12 plus IL-18 during the early differentiation of human umbilical cord blood CD4(+) Th cells. Twenty-six genes were similarly regulated in response to treatment with IL-12, IFN-alpha, or the combination of IL-12 plus IL-18. These genes could therefore play a role in Th1 lineage decision. Transcription factor activating transcription factor (ATF) 3 was upregulated by these cytokines and selected for further study. Ectopic expression of ATF3 in CD4(+) T cells enhanced the production of IFN-gamma, the hallmark cytokine of Th1 cells, whereas small interfering RNA knockdown of ATF3 reduced IFN-gamma production. Furthermore, ATF3 formed an endogenous complex with JUN in CD4(+) T cells induced to Th1. Chromatin immunoprecipitation and luciferase reporter assays showed that both ATF3 and JUN are recruited to and transactivate the IFNG promoter during early Th1 differentiation. Collectively, these data indicate that ATF3 promotes human Th1 differentiation.
77: Immunity, 2010 Mar 18, 10(1)
Interferon-gamma Regulates Intestinal Epithelial Homeostasis through Converging beta-Catenin Signaling Pathways.
[Abstract]Inflammatory cytokines have been proposed to regulate epithelial homeostasis during intestinal inflammation. We report here that interferon-gamma (IFN-gamma) regulates the crucial homeostatic functions of cell proliferation and apoptosis through serine-threonine protein kinase AKT-beta-catenin and Wingless-Int (Wnt)-beta-catenin signaling pathways. Short-term exposure of intestinal epithelial cells to IFN-gamma resulted in activation of beta-catenin through AKT, followed by induction of the secreted Wnt inhibitor Dkk1. Consequently, we observed an increase in Dkk1-mediated apoptosis upon extended IFN-gamma treatment and reduced proliferation through depletion of the Wnt coreceptor LRP6. These effects were enhanced by tumor necrosis factor-alpha (TNF-alpha), suggesting synergism between the two cytokines. Consistent with these results, colitis in vivo was associated with decreased beta-catenin-T cell factor (TCF) signaling, loss of plasma membrane-associated LRP6, and reduced epithelial cell proliferation. Proliferation was partially restored in IFN-gamma-deficient mice. Thus, we propose that IFN-gamma regulates intestinal epithelial homeostasis by sequential regulation of converging beta-catenin signaling pathways.
78: PloS one, 2010, 5(3)
Upregulation of SOCS-3 and PIAS-3 Impairs IL-12-Mediated Interferon-Gamma Response in CD56 T Cells in HCV-Infected Heroin Users.
[Abstract]BACKGROUND: CD56(+) T cells are abundant in liver and play an important role in host innate immunity against viral infections, including hepatitis C virus (HCV) infection, a common infection among heroin abusers. We thus investigated the in vivo impact of heroin use or heroin use plus HCV infection on the CD56(+) T cell frequency and function. METHODOLOGY/PRINCIPAL FINDINGS: A total of 37 heroin users with (17) or without (20) HCV infection and 17 healthy subjects were included in the study. Although there was no significant difference in CD56(+) T cell frequency in PBMCs among three study groups, CD56(+) T cells isolated from the heroin users had significantly lower levels of constitutive interferon-gamma (IFN-gamma) expression than those from the normal subjects. In addition, when stimulated by interleukin (IL)-12, CD56(+) natural T cells from HCV-infected heroin users produced significantly lower levels of IFN-gamma than those from the normal subjects. This diminished ability to produce IFN-gamma by CD56(+) T cells was associated with the increased plasma HCV viral loads in the HCV-infected heroin users. Investigation of the mechanisms showed that although heroin use or heroin use plus HCV infection had little impact on the expression of the key positive regulators (IL-12 receptors, STAT-1, 3, 4, 5, JAK-2, and TYK-2) in IL-12 pathway, heroin use or heroin use plus HCV infection induced the expression of suppressor of cytokine signaling protein-3 (SOCS-3) and protein inhibitors of activated STAT-3 (PIAS-3), two key inhibitors of IL-12 pathway. CONCLUSION/SIGNIFICANCE: These findings provide compelling in vivo evidence that heroin use or heroin use plus HCV infection impairs CD56(+) T cell-mediated innate immune function, which may account for HCV infection and persistence in liver.
79: Antiviral chemistry & chemotherapy, 2010, 20(4)
Induction of interferon-gamma-inducible protein 10 by SARS-CoV infection, interferon alfacon 1 and interferon inducer in human bronchial epithelial Calu-3 cells and BALB/c mice.
[Abstract]BACKGROUND: The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV) is poorly understood. Several mechanisms involving both direct effects on target cells and indirect effects via the immune system might exist. SARS-CoV has been shown in vitro to induce changes of cytokines and chemokines in various human and animal cells. We previously reported that interferon (IFN) alfacon-1 was more active against SARS-CoV infection in human bronchial epithelial Calu-3 cells than in African green monkey kidney epithelial cells on day 3 post-infection. METHODS: In the current study, we first evaluated the efficacy of IFN-alfacon 1 in Calu-3 cells during the first 7 days of virus infection. We then used the two-antibody sandwich ELISA method to detect IFN-gamma-inducible protein 10 (IP-10). We further evaluated the efficacy of antivirals directed against SARS-CoV infection in BALB/c mice. RESULTS: A potent, prolonged inhibition of SARS-CoV replication in Calu-3 cells with IFN-alfacon 1 was observed. Furthermore, IP-10, an IFN-inducible leukocyte chemoattractant, was detected in Calu-3 cells after SARS-CoV infection. Interestingly, IP-10 expression was shown to be significantly increased when SARS-CoV-infected Calu-3 cells were treated with IFN alfacon-1. IP-10 expression was detected in the lungs of SARS-CoV-infected BALB/c mice. Significantly high levels of mouse IP-10 in BALB/c mice was also detected when SARS-CoV-infected mice were treated with the interferon inducer, polyriboinosinic-polyribocytidylic acid stabilized with poly-l-lysine and carboxymethyl cellulose (poly IC:LC). Treatment with poly IC:LC by intranasal route were effective in protecting mice against a lethal infection with mouse-adapted SARS-CoV and reduced the viral lung titres. CONCLUSIONS: Our data might provide an important insight into the mechanism of pathogenesis of SARS-CoV and these properties might be therapeutically advantageous.
80: Journal of acquired immune deficiency syndromes (1999), 2010 Apr 1, 53(4)
Diagnosis of Active Tuberculosis by Enzyme-Linked Immunospot Assay for Interferon-gamma in HIV-Infected Patients.
[Abstract]
81: Investigative ophthalmology & visual science, 2010 Mar 10, 22(3)
Interferon Gamma-inducible Protein (IP-10) and Eotaxin Are Associated with Age-related Macular Degeneration.
[Abstract]Purpose: To analyze serum cytokine levels in subjects with different stages of AMD and to study the expression of salient cytokines in postmortem eyes with AMD. Methods: A Bio-Plex system was used to analyze sera (n = 18 to 20/group) from control subjects and those with AREDS stage 1 (early AMD), AREDS stage 3 (intermediate AMD), advanced AMD with geographic atrophy (GA), or neovascular AMD (CNV). Postmortem eyes with AMD or controls were examined immunohistochemically for expression of IP-10 and eotaxin (n = 4 to 8/group). Results: Serum eotaxin and IP-10 levels were significantly elevated in all stages of AMD except for eotaxin levels in neovascular AMD (P<0.07). The peak of serum IP-10 concentration was at AREDS stage 3. In postmortem eyes, IP-10 and eotaxin expressions were increased in the RPE of eyes with early AMD, GA, and CNV. Eotaxin accumulated within the layer of basal linear/laminar deposits in all stages of AMD, while IP-10 was mainly in eyes with GA and CNV. IP-10 was abundant in the connective tissue matrix associated with CNV, and eotaxin was usually present but more focally and with less intense staining. Both IP-10 and eotaxin were expressed by neovascular endothelial cells. Both IP-10 and eotaxin were expressed in the neurosensory retina, but there was no detectable difference in staining among eyes with or without AMD. Conclusions: IP-10 and eotaxin may be early biomarkers in AMD, and we hypothesize that the relative balance between levels of IP-10 and eotaxin may be critical in regulating the neovascular response.
82: Fundamental & clinical pharmacology, 2010 Feb 22, 10(1)
Regulation of drug transporter mRNA expression by interferon-gamma in primary human hepatocytes.
[Abstract]Abstract Interferon (IFN)-gamma is known to downregulate expression of drug detoxifying proteins such as cytochromes P-450 (CYPs) in human hepatocytes. The present study was designed to determine whether IFN-gamma may also impair expression of influx and efflux drug transporters, which constitute important determinants of the liver detoxification pathway. Exposure of primary human hepatocytes to 10 ng/mL IFN-gamma was found to downregulate mRNA levels of sinusoidal influx transporters such as sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptide (OATP) 2B1, OATP1B1, and OATP1B3. IFN-gamma concomitantly reduced mRNA expression of drug efflux pumps such as multidrug resistance gene 1, multidrug resistance protein (MRP) 2, MRP3, breast cancer resistance protein and bile salt export pump. Such IFN-gamma-mediated repression of major hepatic drug transporters may contribute to impaired liver clearance of drugs administrated to patients suffering from inflammation or viral infections associated with increased secretion of IFN-gamma.
83: The Pediatric infectious disease journal, 2010 Mar, 29(3)
Indeterminate Interferon-gamma Release Assay Results in Children.
[Abstract]PURPOSE: An autoimmune etiology is proposed in some patients with chronic nonbacterial prostatitis since they show interferon-gamma secreting lymphocytes specific to prostate antigens in the periphery and increased interferon-gamma in seminal plasma. We investigated the involvement of interferon-gamma in an animal model of autoimmune prostatitis. MATERIALS AND METHODS: Experimental autoimmune prostatitis was studied in the no-obese diabetic and C57Bl/6 (Harlan, Zeist, The Netherlands) susceptible mouse strains, and in the IRF-1 KO and STAT-1 KO mouse strains deficient in transcription factors involved in interferon-gamma signaling. RESULTS: Experimental autoimmune prostatitis was characterized by prostate specific interferon-gamma secreting cells in the periphery and by T-helper 1 related cytokines in the target organ. Increased interferon-gamma and interleukin-12 were observed in the prostate of autoimmune animals while interleukin-10 and interleukin-4 were decreased and unaltered, respectively. The absence of transcription factors involved in the interferon-gamma signaling cascade, IRF-1 and STAT-1, made mice resistant to experimental autoimmune prostatitis. IRF-1 KO and STAT-1 KO mice immunized with prostate antigens did not show infiltration or alterations in the prostate. They did not have the typical prostate specific autoimmune response and showed decreased interferon-gamma, interleukin-12 and interleukin-10, and augmented interleukin-4 in the prostate. CONCLUSIONS: Our results argue for a crucial role of interferon-gamma as a key factor in the pathogenesis of the disease. Intense research is promptly required to identify the pathogenic mechanisms underlying chronic prostatitis/chronic pelvic pain syndrome to find a more rational therapy.
84: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2010 Feb 28, 104(3)
The Contribution of Interleukin-12/Interferon-gamma Axis in Protection Against Neonatal Pulmonary Chlamydia muridarum Challenge.
[Abstract]Neonatal Chlamydia trachomatis pneumonia has been associated with respiratory sequelae in later life. We recently established a mouse model of neonatal pulmonary Chlamydia muridaum infection and found an important contribution of IFN-gamma to protective immunity. In this study, we further characterized the role of Th1-type cytokines; IL-12, IFN-gamma, and IFN-gamma signaling using mice genetically deficient in IL-12, IFN-gamma, or IFN-gamma receptor 1. All 3 knockout (KO) mice challenged intranasally with C. muridarum 1 day after birth exhibited 100% mortality by day 17 post-challenge whereas wild-type (WT) animals survived the monitoring period of 1 month. The KO mice exhibited greater lung bacterial burdens and enhanced dissemination to the liver, compared to WT animals. The inflammatory cellular infiltration in C. muridarum-challenged KO animals was significantly reduced in the lungs, but markedly enhanced in the livers of the KO mice compared to similarly challenged WT mice. It was also found that a deficiency in IL-12 or IFN-gamma resulted in correspondingly reduced IFN-gamma or IL-12 production, respectively, suggesting an intricate interdependence in the induction of these cytokines. Collectively, these results suggest that the IL-12/ IFN-gamma axis induces pulmonary cellular infiltration, induces bacterial clearance from the lung, reduces dissemination to other organs, and promotes the survival of the host during neonatal pulmonary chlamydial infection.
85: Hepatology (Baltimore, Md.), 2010 May, 51(5)
Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C.
[Abstract]High systemic levels of interferon-gamma-inducible protein 10 kDa (IP-10) at onset of combination therapy for chronic hepatitis C virus (HCV) infection predict poor outcome, but details regarding the impact of IP-10 on the reduction of HCV RNA during therapy remain unclear. In the present study, we correlated pretreatment levels of IP-10 in liver biopsies (n = 73) and plasma (n = 265) with HCV RNA throughout therapy within a phase III treatment trial (DITTO-HCV). Low levels of plasma or intrahepatic IP-10 were strongly associated with a pronounced reduction of HCV RNA during the first 24 hours of treatment in all patients (P < 0.0001 and P = 0.002, respectively) as well as when patients were grouped as genotype 1 or 4 (P = 0.0008 and P = 0.01) and 2 or 3 (P = 0.002, and P = 0.02). Low plasma levels of IP-10 also were predictive of the absolute reduction of HCV RNA (P < 0.0001) and the maximum reduction of HCV RNA in the first 4 days of treatment (P < 0.0001) as well as sustained virological response (genotype 1/4; P < 0.0001). To corroborate the relationship between early viral decline and IP-10, pretreatment plasma samples from an independent phase IV trial for HCV genotypes 2/3 (NORDynamIC trial; n = 382) were analyzed. The results confirmed an association between IP-10 and the immediate reduction of HCV RNA in response to therapy (P = 0.006). In contrast, pretreatment levels of IP-10 in liver or in plasma did not affect the decline of HCV RNA between days 8 and 29, i.e., the second-phase decline, or later time points in any of these cohorts. CONCLUSION: In patients with chronic hepatitis C, low levels of intrahepatic and systemic IP-10 predict a favorable first-phase decline of HCV RNA during therapy with pegylated interferon and ribavirin for genotypes of HCV.
86: Annals of the rheumatic diseases, 2010 Feb 25, 104(3)
Comparison of two interferon{gamma} release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases.
[Abstract]Even though some studies have reported the results of serial interferon-gamma release assays (IGRAs) during isoniazid prophylactic treatment, serial results have not been reported after rifampicin prophylaxis. A contact investigation was conducted after a tuberculosis (TB) outbreak in an accommodation facility. The tuberculin skin test (TST) and the QuantiFERON-TB Gold In-Tube (QFT-GIT) test were performed in 214 contacts with normal chest radiographs. Rifampicin prophylaxis was initiated in TST+/QFT-GIT+ subjects, and the QFT-GIT test was repeated upon completion of 4 months of rifampicin treatment. Among the 214 contacts, the TST and QFT-GIT test results were positive in 67.7% and 56.7%, respectively, and the agreement between the two tests was fair-to-good (78.3%, kappa=0.55, p<0.001). The QFT-GIT test was positive in 77% (97/126) of contacts with positive TST results. Rifampicin prophylaxis was completed in 81 subjects with good compliance. Among 74 subjects with valid serial QFT-GIT test results, IFN-gamma levels decreased in 97.3% (72/74) of the subjects and QFT-GIT test reversion (positive to negative) was achieved in 31 subjects (41.9%). Subjects without QFT-GIT test reversion had a significantly higher baseline TST induration sizes (18.3+/-4.8 vs. 14.9+/-3.4mm, p<0.01) and IFN-gamma levels (18.6+/-17.9 vs. 3.2+/-7.5IU/mL, p<0.01) than the subjects with QFT-GIT test reversion. Thus, IGRAs may be useful in evaluating the therapeutic response to rifampicin prophylaxis in TB contacts. However, considering that this was not a controlled study, a prospective controlled study is needed to determine whether rifampicin prophylaxis truly affects QFT-GIT reversion.
87: Clinical and vaccine immunology : CVI, 2010 Feb 24, 104(3)
Assessment of imprecision in the interferon gamma release assays (IGRA) for the detection of exposure to Mycobacterium tuberculosis.
[Abstract]New interferon gamma release assays (IGRAs) to detect an exposure to Mycobacterium tuberculosis have been recently launched. The majority of the studies in temperate climate countries agree that these methods have superior specificity and equal or even superior sensitivity over Tuberculin Skin Tests (TSTs) in the detection of latent tuberculosis infection (LTBI). However, reproducibility data of IGRAs are virtually missing. We assessed within-run, between-run and total imprecision of two commercial IGRAs by testing samples from subjects with a stable state of tuberculosis (TB) infection, treated pulmonary TB, a healthy volunteer and internal quality control samples. We calculated CV%s to describe assays variability and compared the obtained results to the reported CV%s from other commercial immunodiagnostic methods. We illustrate an example of assay variability near the cut-off zone to demonstrate the necessity of the grey zone. Due to the strict adherence to the standard operation procedures (SOP) adopted in our laboratory the total imprecision of ELISPOT- and EIA-based IGRAs was at max CV% = 37.8% for the samples with moderate and high reactivities. Imprecision of testing samples with very low reactivity levels or non-reactive samples may, however, exceed 100% .In conclusion, despite multiple steps of the method performance, the analytical imprecision of IGRAs which in our study design included also between-lot variability and had a component of normal biological variation, were well in accordance with the reported imprecision for other manual immunodiagnostic tests. The recognition of the variability around the cut-off point advocates the use of the grey zone to avoid ambiguous result interpretations.
88: BMC cancer, 2010 Feb 23, 10(1)
Activated CD4+ T cells enhance radiation effect through the cooperation of interferon-gamma and TNF-alpha.
[Abstract]ABSTRACT: BACKGROUND: Approaches that enhance radiation effect may lead to improved clinical outcome and decrease toxicity. Here we investigated whether activated CD4+ T cells (aCD4) can serve as an effective radiosensitizer. METHODS: CD4+ T cells were activated with anti-CD3 and anti-CD28 mAbs. Hela cells were presensitized with aCD4 or conditioned supernatant (aCD4S) or recombinant cytokines for 2 days, followed gamma-irradiation. The treated cells were cultured for an additional 2 to 5 days for cell proliferation, cell cycle, and western blot assays. For confirmation, other cancer cell lines were also used. RESULTS: Presensitization of tumor cells with aCD4 greatly increased tumor cell growth inhibition. Soluble factors secreted from activated CD4+ T cells were primarily responsible for the observed effect. IFN-gamma seemed to play a major role. TNF-alpha, though inactive by itself, significantly augmented the radiosensitizing activity of IFN-gamma. aCD4S, but not IFN-gamma or IFN-gamma/TNF-alpha combination, was found to enhance the gamma-irradiation-induced G2/M phase arrest. Bax expression was highly upregulated in Hela cells presensitized with aCD4S followed by gamma-irradiation. The radio-sensitizing activity of aCD4 is not uniquely observed with Hela cell line, but also seen with other cancer cell lines of various histology. CONCLUSIONS: Our findings suggest possible molecular and cellular mechanisms that may help explain the radio-sensitization effect of activated lymphocytes, and may provide an improved strategy in the treatment of cancer with radiotherapy.
89: Molecular immunology, 2010 Feb 18, 104(3)
Poly(ADP-ribose) polymerase-1 modulates interferon-gamma-inducible protein (IP)-10 expression in murine embryonic fibroblasts by stabilizing IP-10 mRNA.
[Abstract]Poly(ADP-ribose) polymerase-1 (Parp-1) is a nuclear enzyme that uses NAD(+) as a substrate to catalyze the addition of ADP-ribose polymers on a variety of nuclear proteins, modifying transiently their biological functions. Parp-1 has been involved in transcription regulation of many genes involved in the inflammatory response including cytokines and chemokines. Accordingly, genetic deletion of Parp-1 (Parp-1(-/-)) or pharmacological blockade of Parp-1 activity in mice results in a defective inflammatory immune response which confers an advantage in different pathophysiological conditions associated with inflammation. In addition to the transcriptional control, increasing mRNA stability, mainly through the mitogen-activated protein kinase p38 (p38(MAPK)) might be an important mechanism for the tight regulation in the expression of several chemokines such as IP-10. Here we demonstrate that Parp-1 deficiency in embryonic fibroblasts results in diminished IFN-gamma-induced IP-10 expression despite normal STAT1 activation and IP-10 promoter activity. Therefore, we have analyzed the involvement of Parp-1 in IP-10 mRNA stability. Parp-1 deficient cells showed a decreased half-life of IFN-gamma-induced IP-10 transcripts associated with a defect in p38(MAPK) activation. Our results demonstrate that Parp-1 can regulate inflammatory gene expression by increasing mRNA stability, via modulating a proper p38(MAPK) signalling pathway.
90: Acta dermato-venereologica, 2010 Mar, 90(2)
Development of a Prominent Granulomatous Eruption after Interferon-gamma Therapy in a Patient with Mycosis Fungoides.
[Abstract]
91: Neuroscience, 2010 Feb 12, 116(3)
Morphine preconditioning reduces lipopolysaccharide and interferon-gamma -induced mouse microglial cell injury via delta1 opioid receptor activation.
[Abstract]Microglial cells play an important role in the inflammatory response of a broad range of brain diseases including stroke, brain infection and neurodegenerative diseases. However, there is very little information regarding how to protect microglial cells. Here, we showed that incubation of the C8-B4 mouse microglial cells with lipopolysaccharide (LPS) plus interferon-gamma (IFNgamma) induced cytotoxicity as assessed by the amount of lactate dehydrogenase (LDH) released from the cells. Preconditioning the cells with morphine for 30 min concentration-dependently reduced LPS plus IFNgamma-induced cell injury. This morphine preconditioning effect was abolished by naloxone, a general opioid receptor antagonist, by naltrindole, a selective deltaopioid receptor antagonist and by 7-benzylidenenaltrexone maleate, a selective delta(1) opioid receptor antagonist. However, this protective effect was not affected by ss-funaltrexamine, a selective microopioid receptor antagonist, nor-binaltorphimine, a selective betaopioid receptor antagonist or naltriben, a selective delta(2) opioid receptor antagonist. LPS plus IFNgamma induced the expression of inducible nitric oxide synthase (iNOS), which was not affected by morphine preconditioning. Our results suggest that morphine induced a preconditioning effect in microglial cells. This effect may be mediated by delta1 opioid receptors and may not be through inhibiting the expression of iNOS, a potentially harmful protein.
92: Thorax, 2010 Feb, 65(2)
Interferon gamma-1b does not improve survival for patients with idiopathic pulmonary fibrosis.
[Abstract]Memory of past cellular responses is an essential adaptation to repeating environmental stimuli. We addressed the question whether interferon-gamma (IFNgamma) - inducible transcription generates memory that sensitizes cells to a second stimulus. We have found that the Major Histocompatibility Complex Class II (MHCII) gene DRA is relocated to Promyelocytic leukemia (PML) nuclear bodies upon induction with IFNgamma and this topology is maintained long after transcription shut off. Concurrent interaction of PML protein with Mixed Lineage Leukemia (MLL) generates a prolonged permissive chromatin state on the DRA gene characterized by high promoter histone H3 K4 dimethylation that facilitates rapid expression upon restimulation. We propose that the primary signal-induced transcription generates spatial and epigenetic memory that is maintained through several cell generations and endows the cell with increased responsiveness to future activation signals.
93: Swiss medical weekly : official journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology, 2010 Feb 3, 59(3)
Assessment of an Interferon-gamma release assay for the diagnosis of latent tuberculosis infection in haemodialysis patients.
[Abstract]BACKGROUND: The accurate diagnosis of latent tuberculosis infection (LTBI) in haemodialysis patients remains elusive. Impaired immune function associated with chronic kidney failure causes a high number of anergic tuberculin skin tests (TST). Interferon-gamma (INF-gamma) release assays (IGRAs) measuring the INF-gamma secretion of tuberculosis specific T-cells have several advantages over the TST but their significance in dialysis patients is currently uncertain. METHODS: This study examines the test-performances of the QuantiFERON Gold InTube (QFT-GIT) in a cohort of 39 haemodialysis (HD) patients and 52 healthy individuals. RESULTS: INF-gamma secretion in HD patients was significantly lower than in healthy controls, however, mitogen-anergic QFT-GIT results were only found in 2.6% of HD-patients. INF-gamma secretion was independent of duration of HD treatment, dialysis quality and nutritional status. The QFT-GIT showed a closer association with TB risk factors as a proxy for past exposure to TB than the TST. CONCLUSIONS: We conclude that the QFT-GIT is a valid alternative to the TST. Together with the survey of TB risk factors, it may help to diagnose LTBI more accurately in HD-patients.
94: Innate immunity, 2010 Feb 3, 59(3)
Interferon-gamma secretion is induced in IL-12 stimulated human NK cells by recognition of Helicobacter pylori or TLR2 ligands.
[Abstract]Helicobacter pylori induce a chronic inflammation in the human gastric mucosa characterized by increased production of interferon-gamma (IFN-gamma). The presence of natural killer (NK) cells in the human gastric mucosa and the ability of NK cells to produce IFN-gamma suggest an important role of NK cells in the immune response directed towards H. pylori infection. Since NK cells previously have been shown to respond to bacterial components with IFN-gamma production, we investigated the mechanisms for the recognition of H. pylori. We found that inhibition of MyD88 homodimerization resulted in decreased production of IFN-gamma and that inhibition of the p38 MAPK decreased the production as well as the secretion of IFN-gamma. Further studies indicated an involvement of Toll-like receptors (TLRs), in particular TLR2. Finally, we showed that the H. pylori specific membrane bound lipoprotein HpaA induced IFN-gamma production from NK cells through recognition by TLR2. In conclusion, we suggest an involvement of TLR2 in the recognition of H. pylori by human NK cells and that HpaA is a TLR2 ligand important for recognition.
95: Molecular and cellular biology, 2010 Feb 1, 49(2)
Interferon gamma dependent transcriptional memory via relocalization of a gene locus to PML nuclear bodies.
[Abstract]Memory of past cellular responses is an essential adaptation to repeating environmental stimuli. We addressed the question whether interferon-gamma (IFNgamma) - inducible transcription generates memory that sensitizes cells to a second stimulus. We have found that the Major Histocompatibility Complex Class II (MHCII) gene DRA is relocated to Promyelocytic leukemia (PML) nuclear bodies upon induction with IFNgamma and this topology is maintained long after transcription shut off. Concurrent interaction of PML protein with Mixed Lineage Leukemia (MLL) generates a prolonged permissive chromatin state on the DRA gene characterized by high promoter histone H3 K4 dimethylation that facilitates rapid expression upon restimulation. We propose that the primary signal-induced transcription generates spatial and epigenetic memory that is maintained through several cell generations and endows the cell with increased responsiveness to future activation signals.
96: Journal of dermatological science, 2010 Mar, 57(3)
Keratinocyte differentiation induced by calcium, phorbol ester or interferon-gamma elicits distinct changes in the retinoid signalling pathways.
[Abstract]BACKGROUND: Retinoids influence keratinocyte proliferation and differentiation via binding to nuclear retinoic acid receptors (RARalpha, -gamma) and retinoid X receptor alpha (RXRalpha). The effect of keratinocyte differentiation on expression of nuclear retinoid receptors and on the conversion of retinol into retinoic acid has not been examined earlier in depth. OBJECTIVES: Our aim was to examine the expression of retinoid receptors and a retinoid-regulated gene CRABPII, as well as the metabolism of exogenous [(3)H]retinol in cultured human keratinocytes induced to differentiate by exposure to either calcium, phorbol 12-myristate 13-acetate (PMA), or interferon-gamma (IFNgamma). METHODS: Normal human keratinocytes were cultured and exposed to differentiation-inducing agents. The mRNA and protein expression of retinoid receptors were examined using real-time PCR and Western blot. [(3)H]Retinol uptake and metabolism was monitored by HPLC with on-line radioactivity detection. RESULTS: In calcium-exposed cells, increased expression of RARgamma and RXRalpha, enhanced metabolism of [(3)H]retinol to 3,4-didehydro-RA (ddRA), and an induction of CRABPII mRNA and protein was noted. In contrast, treatment with PMA and IFNgamma reduced the RARgamma and RXRalpha protein expression (preventable by the proteasome inhibitor MG132), increased the accumulation of [(3)H]RA and/or [(3)H]ddRA in the cells, and changed the CRABPII transcription. CONCLUSIONS: Retinoid signalling is profoundly altered upon differentiation of keratinocytes and the effects depend on how cellular differentiation is initiated.
97: Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 2010 Jan 19, 285(4)
T cells from patients with Guillain-Barr¨¦ syndrome produce interferon-gamma in response to stimulation with the ganglioside GM1.
[Abstract]Guillain-Barr¨¦ syndrome (GBS) is an acquired demyelinating neuropathy, characterized by infiltration of peripheral nerves with macrophages and T cells. There have been reports of antibodies to glycolipids in GBS. We have previously found T cell reactivity to glycolipids in patients with the demyelinating form of GBS. This study was performed to characterize the cytokines produced by these T cells. Peripheral blood lymphocytes from patients with GBS, chronic inflammatory demyelinating polyradiculoneuropathy, healthy control patients and other neuropathies were incubated with the ganglioside GM1 and transferred to enzyme-linked immunospot plates. The average number per well of spot-forming cells (SFC) in the absence of antigen was counted. The average spontaneous SFC number was subtracted from the average SFC number in the presence of GM1, to produce a corrected SFC. There was significantly increased production of interferon-gamma but not interleukin-5 in response to stimulation with the ganglioside GM1. This could indicate that SFC have a role in pathogenesis of disease.
98: Human immunology, 2010 Jan 23, 22(1)
Interferon-gamma and T-bet expression in a patient with toxoplasmic lymphadenopathy.
[Abstract]Infection with Toxoplasma gondii (TG) presents in some individuals as a self-limited disease with a predominant lymphadenopathy characterized by prominent B-cell activation. As this is in contrast to the in vitro based concept of a T(h)1-immune response against TG, we investigated native lymphoid tissue and peripheral blood of a patient with serologic evidence of toxoplasmosis to verify which cells show T(h)1-response features. High-level expression of T-bet in monocytoid B-cells, in germinal center B-cells, and in a lesser amount in T cells could be demonstrated by immunohistochemistry. In vitro stimulation of lymph node cells with either TG, staphylococcus enterotoxin B, or phorbol 12-myristate 13-acetate/ionomycin revealed an interferon-gamma expression in T-bet(+) B cells only in the patients and not in controls. Similar results were found for T-bet(+) T cells which were also present in controls. CD4(+) peripheral blood cells stimulated with TG antigens showed a TG-specific but attenuated T(h)1-reactivity in the patient associated with a reduced expression of IL-2 when compared with controls. We conclude that the pathogenesis and course of toxoplasmic lymphadenopathy is based on a T(h)1-cell defect, which becomes compensated by the B cells mounting a T(h)1-like immune response.
99: Journal of virology, 2010 Jan 13, 58(2)
Murine gammaherpesvirus 68 has evolved interferon-gamma and Stat1 repressible promoters for the lytic switch gene 50.
[Abstract]Cytokines regulate viral gene expression with important consequences for viral replication and pathogenesis. Interferon-gamma (IFN-gamma) is a key regulator of chronic murine gammaherpesvirus 68 (gammaHV68) infection and a potent inhibitor of gammaHV68 reactivation from latency. Macrophages are the cell type responsive to IFN-gamma mediated control of gammaHV68 reactivation; however, the molecular mechanism of this IFN-gamma action is undefined. Here we report that IFN-gamma inhibits lytic replication of gammaHV68 in primary bone marrow derived macrophages, and decreases transcript levels for the essential lytic switch gene 50. Interestingly, IFN-gamma suppresses activity of the two known gene 50 promoters, demonstrating that an inflammatory cytokine can directly regulate the promoters for the gammaHV68 lytic switch gene. Stat1, but not IFN-alpha/beta signaling, is required for IFN-gamma action. Moreover, Stat1 deficiency increases basal gammaHV68 replication, gene 50 expression and promoter activity. Together, these data identify IFN-gamma and Stat1 as negative regulators of the gammaHV68 lytic cycle and raise the possibility that gammaHV68 maintains IFN-gamma/Stat1 responsive gene 50 promoters to facilitate cell-extrinsic control over the interchange between the lytic and latent cycle.
100: American journal of reproductive immunology (New York, N.Y. : 1989), 2010 Jan 12, 5(1)
Contribution of Interferon-gamma Receptor 1 Gene Polymorphisms to Pre-Eclampsia in China.
[Abstract]Citation Chen L-J, Gao H, Zhou H, Zou L, Zou P. Contribution of interferon-gamma receptor 1 gene polymorphisms to pre-eclampsia in China. Am J Reprod Immunol 2010 Problem As gene polymorphisms of cytokines receptors have been found to significantly influence cell responses to cytokines, the aim of this study was to test the hypothesis that IFN-gamma receptor 1 (IFNGR1) gene polymorphisms may contribute to the pathogenesis of pre-eclampsia. Method of study One hundred and sixty-four pre-eclamptic patients (121 patients with mild pre-eclampsia and 43 patients with severe pre-eclampsia) and 171 controls were included. Polymorphisms of the IFNGR1 gene at positions -611, -270, +56 and +95 were genotyped with the matrix-assisted laser desorption/ionization time of flight mass spectrometry. Results This study showed a positive association between -56C/C genotype (OR = 1.7; 95% CI = 1.1-2.7) and pre-eclampsia. Although the genotype frequencies (except for -56C/C) of the two polymorphisms were comparable between cases and controls, higher frequency of the -611A/-56C haplotype (OR = 1.450; 95% CI = 1.070-1.966) was noticed in patients versus controls. All patients and controls were homozygous for the -270T/T and +95T/T genotypes. Specifically, the frequency of the -56C allele (OR = 1.838; 95% CI = 1.127-2.995) was higher among patients with severe pre-eclampsia. Conclusion The IFNGR1 gene polymorphisms may contribute to the pathogenesis of pre-eclampsia in our population.
101: The Pediatric infectious disease journal, 2010 Jan 11, 5(1)
Commercial Interferon Gamma Release Assays Compared to the Tuberculin Skin Test for Diagnosis of Latent Mycobacterium tuberculosis Infection in Childhood Contacts in the Gambia.
[Abstract]BACKGROUND:: We compared the performance of tuberculin skin test (TST), Quantiferon-TB Gold in-tube (QFT-GIT), and T-SPOT. TB in diagnosing latent tuberculosis (LTBI) among childhood TB contacts in a TB endemic setting with high BCG coverage. We evaluated the performance of IGRAs and TST when combined in an algorithm. METHODS:: Childhood contacts of newly diagnosed TB patients were tested with TST, QFT-GIT, and T-SPOT. The level of exposure in contacts was categorized according to whether they slept in the same room, same house, or a different house as the index case. For the evaluation of combined test performance, prior estimates for prevalence of latent TB were used in Bayesian models that assumed conditional dependence between tests. RESULTS:: A total of 285 children were recruited. Overall, 26.5%, 33.0%, and 33.5% were positive for TST, T-SPOT, or QFT-GIT, respectively. All 3 tests responded to the gradient of sleeping proximity to the index case. Neither TST nor IGRA results were confounded by BCG vaccination. There was moderate agreement (kappa = 0.40-0.68) between all 3 tests. Combination of either IGRA with TST increased sensitivity (by 9.3%-9.6%) especially in contacts in the highest exposure category but was associated with loss of specificity (9.9%-11.3%). CONCLUSION:: IGRAs and TST are similar in their diagnostic performance for LTBI. An approximate 10% sensitivity benefit for using the TST and an IGRA in combination is associated with a slightly greater specificity loss. Testing strategies combining an IGRA and TST with an "or" statement may be useful only in situations where there is a high pretest probability of latent infection.
102: Archives of neurology, 2010 Jan, 67(1)
Interferon-gamma-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis.
[Abstract]OBJECTIVE: To determine whether fluctuations in functional T-cell subsets can explain why multiple sclerosis (MS) relapses decline during pregnancy and increase in the postpartum period. DESIGN: Case-control study. SETTING: Kaiser Permanente Northern California and Stanford University. PARTICIPANTS: Twenty-six pregnant women with MS and 24 age-matched, pregnant controls. Intervention We prospectively followed up the pregnant women with MS and the age-matched, pregnant controls; conducted structured interviews; and collected peripheral blood mononuclear cells during each trimester and 2, 4, 6, 9, and 12 months post partum. MAIN OUTCOME MEASURES: Sixteen functional cell types, including interferon-gamma (IFN-gamma)- and tumor necrosis factor-producing T-cell subsets, were measured using multicolor flow cytometry. Since these cell types may also fluctuate with pregnancy, lactational amenorrhea, or MS treatment, the data were analyzed taking into account these factors. RESULTS: Fifteen women with MS (58%) had relapses during the postpartum year. CD4(+)IFN-gamma-producing cells fluctuated with MS relapses, declining during pregnancy in women with MS (P < .001) and continuing to decline after parturition in women with relapses (P = .001), yet rising or remaining stable in women with nonrelapsing MS or healthy pregnant women. Lactational amenorrhea was associated with a rise in CD4(+)IFN-gamma-producing cells in women with MS (P = .009). In contrast, CD4(+) tumor necrosis factor-producing cells decreased during lactational amenorrhea in all groups of women and, once this was taken into account, obscured any relationship to MS relapses. CD8(+)IFN-gamma-producing cells were elevated in women with MS throughout the study (P < .001) but did not fluctuate with relapses. CONCLUSIONS: Our findings suggest that a decline in circulating CD4(+)IFN-gamma-producing cells leads to postpartum MS relapses. Our findings also suggest that the decline in these cells may begin during late pregnancy and that lactational amenorrhea induced by exclusive breastfeeding may be able to interrupt this process.
103: Rheumatology international, 2010 Jan 10, 58(2)
Etanercept treatment reduces the serum levels of interleukin-15 and interferon-gamma inducible protein-10 in patients with rheumatoid arthritis.
[Abstract]Tumor necrosis factor-alpha (TNF-alpha) has an essential role in the pathogenesis of rheumatoid arthritis (RA) and has been known to induce the production of several inflammatory molecules in vivo. To analyze in vivo the active mechanism of the TNF-alpha blocking agent, etanercept, the serum levels of the cytokine interleukin-15 (IL-15) and the chemokines growth-regulated protein-alpha (Gro-alpha), and interferon-gamma inducible protein-10 (IP-10) in RA patients were measured. Twenty-two patients with RA were administered etanercept once or twice a week for more than 6 months. The clinical and laboratory parameters were measured and serum levels of IL-15, Gro-alpha, and IP-10 were determined using enzyme-linked immunosorbent assay (ELISA) kits at the baseline and at 3 and 6 months after the initial treatment. Additionally, the production of IL-15 and IP-10 by cultured synovial cells stimulated with TNF-alpha from RA patients was determined by ELISA. A significant decrease in serum levels of IL-15 and IP-10 was observed at 3 and 6 months after initial treatment with etanercept, but not in those of Gro-alpha. TNF-alpha induced production of IP-10, but not IL-15 in cultured synovial cells from RA patients. This study demonstrated for the first time the reduction of IP-10 and IL-15 production in RA patients as active mechanisms of etanercept.
104: The American journal of pathology, 2010 Jan 7, 58(2)
Pulmonary Infection with an Interferon-{gamma}-Producing Cryptococcus neoformans Strain Results in Classical Macrophage Activation and Protection.
[Abstract]Alternative macrophage activation is associated with exacerbated disease in murine models of pulmonary cryptococcosis. The present study evaluated the efficacy of interferon-gamma transgene expression by Cryptococcus neoformans strain H99gamma in abrogating alternative macrophage activation in infected mice. Macrophage recruitment into the lungs of mice after infection with C. neoformans strain H99gamma was comparable with that observed in mice challenged with wild-type C. neoformans. However, pulmonary infection in mice with C. neoformans strain H99gamma was associated with reduced pulmonary fungal burden, increased pulmonary Th1-type and interleukin-17 cytokine production, and classical macrophage activation as evidenced by increased inducible nitric oxide synthase expression, histological evidence of enhanced macrophage fungicidal activity, and resolution of inflammation. In contrast, progressive pulmonary infection, enhanced Th2-type cytokine production, and the induction of alternatively activated macrophages expressing arginase-1, found in inflammatory zone 1, Ym1, and macrophage mannose receptor were observed in the lungs of mice infected with wild-type C. neoformans. These alternatively activated macrophages were also shown to harbor highly encapsulated, replicating cryptococci. Our results demonstrate that pulmonary infection with C. neoformans strain H99gamma results in the induction of classically activated macrophages and promotes fungal clearance. These studies indicate that phenotype, as opposed to quantity, of infiltrating macrophages correlates with protection against pulmonary C. neoformans infection.
105: Scandinavian journal of infectious diseases, 2010, 42(1)
Interferon-gamma gene and interferon-gamma receptor-1 gene polymorphisms in children with tuberculosis from Turkey.
[Abstract]Macrophage activation by interferon-gamma (IFN-gamma) is important in host resistance to tuberculosis (TB). In this study, the relationships of the +874 T/A polymorphism in the first intron of the IFN-gamma gene and intronic (CA)n polymorphic microsatellite marker of the interferon-gamma receptor 1 (IFN-gammaR1) gene to TB susceptibility were investigated in children. Forty children with TB and 67 age-matched controls were included. There were no significant differences between the allele frequencies and genotype frequencies of patient and control groups for the polymorphism +874 T/A in the IFN-gamma gene. Differences that were not statistically significant were found between the group of children with TB and the control group for the allelic markers (170 and 180) in the IFN-gammaR1 gene. The incidence of the allele 170 was higher in patients (30.9%) than in controls (17.4%), whereas the allele 180 was found to be more common in controls (9% vs 1.2%). In conclusion, no significant association was observed between the +874 T/A polymorphism found in the first exon of the IFN-gamma gene and TB susceptibility in Turkish children.
106: Journal of virology, 2009 Dec 30, 351(1-2)
Interferon gamma signaling in oligodendrocytes is critical for protection from neurotropic coronavirus infection.
[Abstract]Neurotropic coronavirus induces acute encephalomyelitis and demyelination in mice. Infection of BALB/c (H-2(d)) mice expressing a dominant-negative IFN-gamma receptor specifically in oligodendrocytes was examined to determine the influence of IFN-gamma signaling on pathogenesis. Inhibition of IFN-gamma signaling in oligodendrocytes increased viral load, infection of oligodendrocytes, oligodendrocyte loss, demyelination and axonal damage resulting in increased mortality. IFN-gamma levels and the inflammatory response were not altered, although TNF mRNA was increased. These data indicate that IFN-gamma signaling by oligodendroglia reduces viral replication, but affects both demyelination and tissue destruction in a host specific manner.
107: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2009 Dec 29, 351(1-2)
Abnormalities in Intracellular Processing and Expression of Interferon-gamma Receptor in Adherent Cells From Lepromatous Leprosy Patients.
[Abstract]Peripheral blood mononuclear cells in lepromatous leprosy (LL) patients produce low levels of interferon-gamma (IFN-gamma) and interleukin-12 (IL-12), and these cells exhibit partial or complete deficiency in the IL-12 receptor. The behavior of the IFN-gamma receptor (IFN-gammaR) has not been described in cells from people with leprosy. We found higher levels of mRNA for IFN-gammaR1 and IFN-gammaR2 in adherent cells stimulated with IFN-gamma and Mycobacterium leprae membrane proteins from LL patients compared with healthy subjects. Flow cytometry showed no significant difference in IFN-gammaR1 expression between LL patients and healthy subjects. Immunoblotting detected only the mature glycosylated form of the 61-67 kDa IFN-gammaR2 protein in healthy subjects. In contrast, cells from LL patients showed three different expression patterns: (1) the immature deglycosylated form of the 34.8 kDa IFN-gammaR2 protein, (2) the mature glycosylated 61-67 kDa form, and (3) both forms. Our data indicate the existence of abnormalities in the intracellular processing and protein expression of the IFN-gammaR in response to specific stimuli such as IFN-gamma and M. leprae membrane proteins in adherent cells of LL patients.
108: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2009 Dec 28, 164(4)
Differential Transcriptional Responses to Interferon-alpha and Interferon-gamma in Primary Human Hepatocytes.
[Abstract]Interferon (IFN) plays a central role in the innate and adaptive antiviral immune responses. While IFN-alpha is currently approved for treating chronic hepatitis B and hepatitis C, in limited studies, IFN-gamma has not been shown to be effective for chronic hepatitis B or C. To identify the potential mechanism underlying the differential antiviral effects of IFN-alpha and IFN-gamma, we used cDNA microarray to profile the global transcriptional response to IFN-alpha and IFN-gamma in primary human hepatocytes, the target cell population of hepatitis viruses. Our results reveal distinct patterns of gene expression induced by these 2 cytokines. Overall, IFN-alpha induces more genes than IFN-gamma at the transcriptional level. Distinct sets of genes were induced by IFN-alpha and IFN-gamma with limited overlaps. IFN-alpha induces gene transcription at an early time point (6 h) but not at a later time point (18 h), while the effects of IFN-gamma are more prominent at 18 h than at 6 h, suggesting a delayed transcriptional response to IFN-gamma in the hepatocytes. These findings indicate differential actions of IFN-alpha and IFN-gamma in the context of therapeutic intervention for chronic viral infections in the liver.
109: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2009 Dec 28, 164(4)
Rare Human IFNG Variants.
[Abstract]After the identification of the human interferon-gamma (IFNG) variant G54D (c.287G>A, ss105106770) in DNA samples from Ghana, West Africa, systematic mutation screening of IFNG by the LightCycler((R))-based procedure of high-resolution melting (HRM) revealed additional rare mutations. All variants occurred heterozygously only and were confirmed either by their detection in other individuals and/or by repeated DNA sequencing of independent PCR products.
110: Chronobiology international, 2009 Dec, 26(8)
PLASMA LEVELS OF INTERFERON-gamma CORRELATE WITH AGE-RELATED DISTURBANCES OF CIRCADIAN RHYTHMS AND SURVIVAL IN A NON-HUMAN PRIMATE.
[Abstract]Aging can be associated with changes in circadian rhythms and reduction in adaptive immune responses accompanied by expansion of memory T cells and elevated levels of pro-inflammatory cytokines. Recent findings suggest the cytokine interferon-gamma (IFN-gamma) can affect the function of the hypothalamic suprachiasmatic nucleus (SCN), the master mammalian circadian pacemaker, both in vitro and in vivo. We studied the correlation of plasma levels of IFN-gamma and changes in circadian rhythms in a non-human primate species, the nocturnal mouse lemur (Microcebus murinus). Plasma IFN-gamma and dehydroepiandrosterone sulfate (DHEA-S), a known biomarker of aging, were determined in middle- to old-age animals by immunoenzymoassay. Daily rhythms of locomotor activity and body temperature as well as survival time of the lemurs were recorded. With aging, mean levels of DHEA-S decreased whereas IFN-gamma increased. Aged animals showed biological rhythm alterations characterized by a high percentage of diurnal activity, anticipation of the activity onset relative to lights-off, short free-running period, and delayed occurrence of minimal body temperature. The magnitude of these disturbances was correlated with the plasma level of IFN-gamma but not DHEA-S. Most remarkably, in contrast to DHEA-S, increased levels of IFN-gamma correlated with duration of the lifetime of the lemurs. These results show the degree of circadian rhythm alterations in an individual is correlated with plasma IFN-gamma level during aging, and that plasma IFN-gamma level may predict survival, at least in this non-human primate. (Author correspondence: fabienne.aujard@wanadoo.fr ).
111: PloS one, 2009, 4(12)
Allergen challenge induces ifng dependent GTPases in the lungs as part of a Th1 transcriptome response in a murine model of allergic asthma.
[Abstract]According to the current paradigm, allergic airway inflammation is mediated by Th2 cytokines and pro-inflammatory chemokines. Since allergic inflammation is self-limited, we hypothesized that allergen challenge simultaneously induces anti-inflammatory genes to counter-balance the effects of Th2 cytokines and chemokines. To identify these putative anti-inflammatory genes, we compared the gene expression profile in the lungs of ragweed-sensitized mice four hours after challenge with either PBS or ragweed extract (RWE) using a micro-array platform. Consistent with our hypothesis, RWE challenge concurrently upregulated Th1-associated early target genes of the Il12/Stat4 pathway, such as p47 and p65 GTPases (Iigp, Tgtp and Gbp1), Socs1, Cxcl9, Cxcl10 and Gadd45g with the Th2 genes Il4, Il5, Ccl2 and Ccl7. These Th1-associated genes remain upregulated longer than the Th2 genes. Augmentation of the local Th1 milieu by administration of Il12 or CpG prior to RWE challenge further upregulated these Th1 genes. Abolition of the Th1 response by disrupting the Ifng gene increased allergic airway inflammation and abrogated RWE challenge-induced upregulation of GTPases, Cxcl9, Cxcl10 and Socs1, but not Gadd45g. Our data demonstrate that allergen challenge induces two sets of Th1-associated genes in the lungs: 1) Ifng-dependent genes such as p47 and p65 GTPases, Socs1, Cxcl9 and Cxcl10 and 2) Ifng-independent Th1-inducing genes like Gadd45g. We propose that allergen-induced airway inflammation is regulated by simultaneous upregulation of Th1 and Th2 genes, and that persistent unopposed upregulation of Th1 genes resolves allergic inflammation.
112: Chest, 2009 Dec 18, 4(12)
Evidence based comparison of commercial interferon-gamma release assays for detecting active tuberculosis -- a meta-analysis.
[Abstract]BACKGROUND: Test accuracy of interferon-gamma release assays (IGRAs) for diagnosing tuberculosis (TB) differs when utilizing older or pre-commercial tools and inconsistent diagnostic criteria. This meta-analysis critically appraises studies investigating sensitivity and specificity of the commercial T-Spot. TB and the in tube version of QuantiFERON-TB Gold (QFT-IT) among definitely confirmed TB cases. METHODS: We searched Medline, EMBASE and Cochrane bibliographies of relevant articles. Sensitivities, specificities and indeterminate rates were pooled using a fixed effect model. Sensitivity of the tuberculin skin test (TST) was evaluated in the context of IGRA studies. In addition, the rates of indeterminates of both IGRAs were assessed. RESULTS: The pooled sensitivity of TST was 70% [95% CI 0.67 to 0.72] compared with 81% [95% CI 0.78 to 0.83] for the QFT-IT and 88% [95% CI 0.86 to 0.90] for the T-SPOT.TB. Sensitivity increased to 84% [95%CI 0.81 to 0.87] and 90% [0.87 to 0.92] for the QFT-IT and T-Spot.TB, respectively, when restricted to performance in developed countries. In contrast, specificity of the QFT-IT was 99% [95% CI 0.98 to 1.00] versus 88% for the T-Spot. TB [0.84 to 0.91]. The pooled rate of indeterminate results was low, 2.1% [95% CI 0.02-0.023] for the QFT-IT and 3.8% [95% CI 0.035-0.042] for the T-Spot.TB, increasing to 4.4% [95% CI 0.039 to 0.05]) and 6.1% [95% CI 0.052 to 0.071], respectively, among immunosuppressed hosts. CONCLUSIONS: Newest commercial IGRAs are superior, in comparison to the TST, for detecting confirmed active TB disease, especially when performed in developed countries.
113: AIDS (London, England), 2009 Dec 10, 132(2-4)
Comparison of interferon gamma and interferon gamma-inducible protein-10 secretion in HIV-tuberculosis patients.
[Abstract]Interferon gamma (IFNgamma)-based in-vitro assays have suboptimal sensitivity, especially in immunocompromised individuals, which emphasizes the need for alternative markers for tuberculosis (TB) diagnosis. We compared TB antigens-specific IFNgamma and IFNgamma-inducible protein-10 levels in culture of whole blood samples from HIV-TB patients. We report that IFNgamma-inducible protein-10 detects a greater number of HIV-TB cases than IFNgamma and suggest that IFNgamma-inducible protein-10 may be a better alternative marker for latent TB infection diagnosis among immunocompromised individuals.
114: Veterinary immunology and immunopathology, 2010 May 15, 135(1-2)
Antiviral effect of recombinant equine interferon-gamma on several equine viruses.
[Abstract]Recombinant equine interferon-gamma (reIFN-gamma) was prepared using a baculovirus expression system and its antiviral activity was investigated using several equine viruses. The reIFN-gamma suppressed the replication of all equine viruses used in the present experiment in horse cell cultures, but did not affect the growth of host cells at concentrations of less than 1000 u/ml. A strong antiviral effect was observed, especially against RNA viruses. Equine picornavirus, equine rhinovirus and equine arteritis virus could not be propagated at all in 100 u/ml reIFN-gamma when 100 TCID(50) of infective viruses was inoculated to cultivated horse cells. DNA viruses, equine herpesvirus types 1, 2, 3 and 4 and equine adenovirus, were less sensitive to reIFN-gamma but their growth became less than 1/100 in the cells treated with 100 u/ml reIFN-gamma compared to untreated cells. The antiviral effects were decreased in the cells of heterologous species and more than 1000 u/ml reIFN-gamma was required to induce an antiviral effect.
115: Brain, behavior, and immunity, 2009 Dec 8, 132(2-4)
Interferon-gamma deficiency modifies the effects of a chronic stressor in mice: implications for psychological pathology.
[Abstract]Pro-inflammatory cytokines promote behavioral and neurochemical variations similar to those evident following stressor exposure, and have been implicated in promoting depressive illness. Indeed, immunotherapeutic application of the cytokine, interferon-alpha, promoted depressive illness in cancer and hepatitis C patients. We assessed the possibility that another interferon cytokine family member, interferon-gamma (IFN-gamma), might contribute to the behavioral and biochemical alterations provoked by a chronic stressor regimen that has been used to model neuropsychiatric pathology in rodents. As predicted, IFN-gamma-deficient mice displayed basal differences in behavior (e.g., reduced open field exploration) and altered neurochemical activity (e.g., increased noradrenergic and serotonergic activity within the central amygdala), relative to their wild-type counterparts. Moreover, stressor-induced elevations of corticosterone and the pro-inflammatory cytokine, tumor necrosis factor-alpha, were attenuated in IFN-gamma-deficient mice. Similarly, the IFN-gamma null mice were refractory to the chronic stressor-induced alterations of dopamine metabolism (within the prefrontal cortex, paraventricular nucleus of the hypothalamus and central amygdala) evident in wild-type mice. Yet, the chronic stressor provoked signs of anxiety (e.g., reduced open field exploration) and depression-like behavior (e.g., increased forced swim immobility, reduced consumption of a palatable solution) among both wild-type and IFN-gamma knockout mice alike, suggesting a dissociation of behavioral functioning from the stressor-induced alterations of immunological, hormonal and dopaminergic activity. Together, these data suggest a complex neurobehavioral phenotype, wherein IFN-gamma deletion engenders a state of heightened basal emotionality coupled with increased monoaminergic activity in the amygdala. At the same time, however, IFN-gamma deficiency appears to blunt some of the neurochemical, corticoid and cytokine alterations ordinarily associated with chronic stressor exposure.
116: Gastroenterology, 2010 Apr, 138(4)
Tumor Necrosis Factor and Interferon-gamma Down-regulate Klotho in Mice With Colitis.
[Abstract]BACKGROUND & AIMS: Klotho (KL) is an anti-inflammatory protein that protects the endothelium from nitric oxide (NO)-induced dysfunction, reduces the expression of endothelial adhesion molecules, and potentially regulates T-cell functions. KL deficiency leads to premature senescence and impaired Ca2+/Pi homeostasis, which can lead to inflammatory bowel disease (IBD)-associated osteopenia/osteoporosis. We investigated the changes in renal expression of Kl as a consequence of colitis. METHODS: We studied 3 mouse models of IBD: colitis induced by trinitrobenzene sulfonic acid, colitis induced by microflora (in gnotobiotic interleukin-10(-/-)), and colitis induced by adoptive transfer of CD4(+)CD45RB(high) T cells. Effects of the tumor necrosis factor (TNF) and interferon (IFN)-gamma on Kl expression and the activity of its promoter were examined in renal epithelial cells (mpkDCT4 and mIMCD3). RESULTS: Renal expression of Kl messenger RNA (mRNA) and protein was reduced in all 3 models of IBD. Reduced level of KL correlated with the severity of colitis; the effect was reversed by neutralizing antibodies against TNF. In vitro, TNF inhibited Kl expression, an effect potentiated by IFN-gamma. The combination of TNF and IFN-gamma increased expression of inducible nitric oxide synthase (iNOS) and increased NO production. The effect of IFN-gamma was reproduced by exposure to an NO donor and reversed by the iNOS inhibitor. In cells incubated with TNF and/or IFN-gamma, Kl mRNA stability was unaffected, whereas Kl promoter activity was reduced, indicating that these cytokines regulate Kl at the transcriptional level. CONCLUSIONS: The down-regulation of KL that occurs during inflammation might account for the extraintestinal complications such as abnormalities in bone homeostasis that occur in patients with IBD.
117: Cytokine, 2009 Dec 7, 132(2-4)
Interferon gamma gene +874A/T polymorphism and intracellular interferon gamma expression in pulmonary tuberculosis.
[Abstract]We investigated whether IFN-gamma gene +874(A/T) polymorphism influences intracellular interferon gamma expression in T-cell subsets of normal healthy subjects (NHS) and pulmonary tuberculosis patients (PTB). Peripheral blood mononuclear cells were stimulated with live Mycobacterium tuberculosis (MTB) and the intracellular IFN-gamma expression was studied using flow cytometry. Genotyping of IFN-gamma gene +874(A/T) was done using allele specific polymerase chain reaction. Significantly increased IFN-gamma expressing CD3+CD4+ and CD3+CD8+ T cells were observed in NHS with AA genotype compared to TT genotype in unstimulated (p=0.0308 and p=0.0157) and MTB stimulated (p=0.0494 and p=0.0287) cultures and this difference was not observed in PTB patients. The present study suggests that the variant genotypes of IFN-gamma (+874) may be associated with altered expression of IFN-gamma at the intracellular level and play an immunoregulatory role at the site of M. tuberculosis infection.
118: BMC infectious diseases, 2009 Dec 15, 9(1)
Performance of the tuberculin skin test and interferon-gamma release assay for detection of tuberculosis infection in immunocompromised patients in a BCG-vaccinated population.
[Abstract]ABSTRACT: BACKGROUND: Interferon-gamma release assay (IGRA) may improve diagnostic accuracy for latent tuberculosis infection (LTBI). This study compared the performance of the tuberculin skin test (TST) with that of IGRA for the diagnosis of LTBI in immunocompromised patients in an intermediate TB burden country where BCG vaccination is mandatory. METHODS: We conducted a retrospective observational study of patients given the TST and an IGRA, the QuantiFERON-TB Gold In-Tube (QFT-IT), at Severance Hospital, a tertiary hospital in South Korea, from December 2006 to May 2009. RESULTS: Of 211 patients who underwent TST and QFT-IT testing, 117 (55%) were classified as immunocompromised. Significantly fewer immunocompromised than immunocompetent patients had positive TST results (10.3% vs. 27.7%, p 0.001), whereas the percentage of positive QFT-IT results was comparable for both groups (21.4% vs. 25.5%). However, indeterminate QFT-IT results were more frequent in immunocompromised than immunocompetent patients (21.4% vs. 9.6%, p 0.021). Agreement between the TST and QFT-IT was fair for the immunocompromised group (kappa = 0.38), but moderate agreement was observed for the immunocompetent group (kappa = 0.57). Indeterminate QFT-IT results were associated with anaemia, lymphocytopenia, hypoproteinemia, and hypoalbuminemia. CONCLUSION: In immunocompromised patients, the QFT-IT may be more sensitive than the TST for detection of LTBI, but it resulted in a considerable proportion of indeterminate results. Therefore, both tests may maximise the efficacy of screening for LTBI in immunocompromised patients.
119: Allergy, 2010 Jun 1, 65(6)
Interferon-gamma and IL-10 may protect from allergic polysensitization in children: preliminary evidence.
[Abstract]Background: A functional defect of T regulatory cells (Treg) has been proposed as pathogenic mechanism of allergic reaction. Polysensitization is a common feature of allergic patients. Aim of the study: It was to investigate the possible role of Treg-Th1 cytokines, in the development of new sensitizations in childhood. Methods: Forty monosensitized (MS) children with allergic rhinitis were evaluated and followed-up for 2 years. New sensitizations were investigated. IL-10 and IFN-gamma were evaluated in in vitro experiments. Results: Children remaining MS showed significant higher production of both IL-10 and IFN-gamma. Conclusion: This preliminary study provided evidence that IL-10 and IFN-gamma production could be defective in allergic children prone to develop polysensitization.
120: Current opinion in pediatrics, 2009 Dec 1, 132(2-4)
Interferon-gamma release assays: new diagnostic tests for Mycobacterium tuberculosis infection, and their use in children.
[Abstract]PURPOSE OF REVIEW: The testing and treatment of children at risk for Mycobacterium tuberculosis infection represents an important public health priority in the United States. Until recently, diagnosis has relied upon the tuberculin skin test (TST). New interferon-gamma release assays (IGRAs) offer improvements over TST, but these tests have not been studied in children until recently. RECENT FINDINGS: Evidence regarding IGRA performance in children is accumulating rapidly. Overall, the findings demonstrate performance of IGRAs equivalent or superior to that of the TST. However, IGRAs have biological limitations similar to TST and some technical problems of their own, and critical gaps in our knowledge remain. SUMMARY: Current evidence supports usage of IGRAs in children aged 5 years or older. IGRAs are preferred over TST when specificity is paramount or wherein patients might fail to return for TST reading. Evidence for use in children aged less than 5 years is insufficient at this time: the sensitivity is poorly defined, and TST is preferred for testing these children. Future IGRA research should focus on children aged less than 5 years for informing expanded usage in this vulnerable population.
121: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology, 2009 Dec, 34(6)
Tuberculosis screening in Portuguese healthcare workers using the tuberculin skin test and the interferon-{gamma} release assay.
[Abstract]The prevalence of latent tuberculosis (TB) infection (LTBI) and the incidence of active tuberculosis in healthcare workers (HCWs) in a Portuguese hospital were examined. This cross-sectional study comprises 4,735 hospital workers screened between May 2005 and September 2008. Tuberculin skin test (TST) and interferon-gamma release assay (IGRA) were used simultaneously in 1,219 HCWs (25.7%). Radiographs were taken in symptomatic HCWs or in test-positive HCWs. The tests were repeated annually or bi-annually depending on risk assessment. IGRA was positive in 32.6% and TST in 74.2% of the HCWs. Years spent in healthcare were a risk factor for a positive IGRA, but not for a positive TST. Repeated bacillus Calmette-Gu¨¦rin vaccination increased the probability of TST+/IGRA- discordance (35.4% versus 54.4%, respectively). In those tested three times with TST during the study period (n = 59), the mean diameter of TST increased from 5 to 7 to 10 mm. Within 3 yrs, 31 HCWs were diagnosed with active TB (annual incidence rate 191 out of 100,000 people). In eight HCWs with active TB, TST and IGRA were performed at the time of diagnosis and each test was positive. TB burden in HCWs in Portugal is high. With IGRA, the number of radiographs needed to exclude active TB could have been reduced by about half without missing a case of active TB. Therefore IGRA should be introduced into TB screening programmes.
122: Neurosurgery clinics of North America, 2010 Jan, 21(1)
Interferon-gamma in Brain Tumor Immunotherapy.
[Abstract]Interferon-gamma (IFNgamma) is a cytokine that acts on cell-surface receptors, activating transcription of genes that offer treatment potential by increasing tumor immunogenicity, disrupting proliferative mechanisms, and inhibiting tumor angiogenesis. However, abnormally low levels of IFNgamma are produced by tumor cells and local T cells in the glioma microenvironment. Current investigations into the immunomodulating effects of IFNgamma suggest that IFNgamma has the potential to be used clinically in the treatment of brain tumors and as a promising adjunct to other immunotherapeutic modalities. Here the authors review the published literature that highlights the potential role of IFNgamma in the treatment and immunotherapy of malignant gliomas.
123: Epilepsy research, 2010 Feb, 88(2-3)
Effect of intravenous immunoglobulin treatment on brain interferon-gamma and interleukin-6 levels in a rat kindling model.
[Abstract]Many studies indicate that intravenous immunoglobulin (IgG) therapy may decrease symptoms of epilepsy. In this study, we assessed the effects of intravenous IgG in an experimental rat kindling model and attempted to elucidate the underlying mechanism of the IgG effect. For induction of kindling, Wistar rats received repeated intraperitoneal injections of picrotoxin. The serum level of neuron-specific enolase (NSE) was measured to determine seizure severity. Interferon (IFN)-gamma and interleukin (IL)-6 levels were measured in rat hippocampus homogenates. The serum NSE level and hippocampal IFN-gamma level were significantly higher in fully kindled, untreated rats compared to unkindled control rats, whereas IL-6 levels were similar in all groups. Intravenous IgG-treated kindled rats showed NSE and IFN-gamma levels similar to those of control rats, along with lower seizure severity and longer seizure latent period than fully kindled, untreated rats. These results indicate that intravenous immunoglobulin exerts a protective effect on the neurons of kindled rats, potentially by downregulating cytokines in the brain. These results shed light on the mechanism by which intravenous immunoglobulin decreases the severity of epileptic seizures.
124: The Journal of biological chemistry, 2010 Jan 22, 285(4)
Ikaros silences T-bet expression and interferon-gamma production during T helper 2 differentiation.
[Abstract]CD4+ T cells can be instructed by nonantigen-specific signals to differentiate into functionally distinct lineages with mutually exclusive patterns of cytokine production. The molecular events that drive interferon-gamma (IFN gamma) production during Th1 development are well understood, but mechanisms that silence this cytokine during Th2 polarization are not clear. In this study, we find that the tbx21 gene encoding the Th1 master regulator T-bet is a direct target of the transcriptional repressor Ikaros. In Th2 cells, which do not express T-bet, strong Ikaros binding could be detected at the endogenous tbx21 promoter, whereas this gene was not occupied by Ikaros in T-bet-expressing Th1 cells. Inhibition of Ikaros DNA binding activity during Th2 polarization resulted in loss of Ikaros promoter occupancy, increased T-bet expression, and inappropriate T-bet-dependent production of IFN gamma. Ikaros was also required for epigenetic imprinting of the ifn gamma locus during Th2 polarization, and loss of Ikaros function in vivo led to an inappropriate Th1 response to the parasite Shistosoma mansoni. These studies demonstrate that Ikaros, a factor with an established role in lymphocyte development, also regulates the development of peripheral T helper responses.
125: The Journal of rheumatology, 2009 Nov 16, 87(3)
Serum Concentrations of Interleukin 1{beta}, CXCL10, and Interferon-{gamma} in Mixed Cryoglobulinemia Associated with Hepatitis C Infection.
[Abstract]OBJECTIVE: Mixed cryoglobulinemia (MC) is a systemic vasculitis of small and medium-size vessels, often associated with the hepatitis C virus. Research has shown an emerging role for chemokines and type 1 cytokines in the pathophysiology of this vasculitis. Interleukin 1 (IL-1) plays a role in initiating the cascade of immunoinflammatory responses, and levels of the interferon-gamma (IFN-gamma) inducible chemokine CXCL10 have been shown to be significantly associated with the presence of active vasculitis in patients with MC. We evaluated serum levels of IL-1ss, IFN-gamma, and CXCL10 in a series of patients with hepatitis C-related MC (MC+HCV), and correlated these measurements with clinical disease features. METHODS: Serum IL-1ss, IFN-gamma, and CXCL10 were assayed in 54 patients with MC+HCV, in 54 sex- and age-matched patients with type C chronic hepatitis without cryoglobulinemia (HCV+), and in 54 controls. RESULTS: MC+HCV patients showed significantly higher mean IL-1ss and CXCL10 serum levels than controls (p < 0.01) or HCV+ patients (p < 0.01). CXCL10 was significantly increased in 14 cryoglobulinemic patients with active vasculitis (necrotizing vasculitis or vasculitic skin ulcers) compared to those without (p < 0.001); IL-1ss was increased in cryoglobulinemic patients with active vasculitis (p = 0.06). No differences were observed for serum IFN-gamma levels. CONCLUSION: Serum levels of IL-1ss and CXCL10 were high in patients with MC+HCV. Increased CXCL10 and IL-1ss levels were associated with the presence of active vasculitis in MC+HCV patients.
126: Proceedings of the National Academy of Sciences of the United States of America, 2009 Nov 11, 284(46)
Acute in vivo exposure to interferon-{gamma} enables resident brain dendritic cells to become effective antigen presenting cells.
[Abstract]Dendritic cells (DC) are the professional antigen presenting cells (APC) that bridge the innate and adaptive immune system. Previously, in a CD11c/EYFP transgenic mouse developed to study DC functions, we anatomically mapped and phenotypically characterized a discrete population of EYFP(+) cells within the microglia that we termed brain dendritic cells (bDC). In this study, we advanced our knowledge of the function of these cells in the CD11c/EYFP transgenic mouse and its chimeras, using acute stimuli of stereotaxically inoculated IFNgamma or IL-4 into the CNS. The administration of IFNgamma increased the number of EYFP(+)bDC but did not recruit peripheral DC into the CNS. IFNgamma, but not IL-4, upregulated the expression levels of major histocompatibility class II (MHC-II). In addition, IFNgamma-activated EYFP(+)bDC induced antigen-specific na?ve CD4 T cells to proliferate and secrete Th1/Th17 cytokines. Activated bDC were also able to stimulate na?ve CD8 T cells. Collectively, these data reveal the Th1 cytokine IFNgamma, but not the Th2 cytokine IL4, induces bDC to up-regulate MHC-II and become competent APC.
127: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2009 Nov 10, 284(46)
Validity of interferon-gamma-release assays for the diagnosis of latent tuberculosis in haemodialysis patients.
[Abstract]Clin Microbiol InfectAbstract Haemodialysis patients are at higher risk of developing active tuberculosis (TB) infection. However, tuberculin skin tests (TST) have limitations and the diagnostic usefulness of interferon-gamma-release assays (IGRAs) remains unclear in immunocompromised hosts including haemodialysis patients. Haemodialysis patients were enrolled from a dialysis centre in Korea, an intermediate TB-burden country with a high bacille Calmette-Gu¨¦rin (BCG) vaccination rate. The QuantiFERON-Gold TB In tube test((R)) (QFT) and the T-SPOT TB test((R)) (TSPOT) were performed, along with the TST. We stratified patients to low- and high-risk groups, according to the risk factors for latent TB. Association between each of the three diagnostic tests and the risk of latent TB was analysed. One hundred and sixty-seven patients were enrolled. The positive rates for the TST, the QFT and TSPOT were 23.5, 45.9 and 60.4%, respectively. Previous BCG vaccination increased the TST-positive rate in the low-risk group (OR 4.438), whereas it affected neither QFT nor TSPOT. The positive QFT rates were 41.2 and 62.5% in the low- and high-risk groups, respectively. The QFT was associated with the high-risk group (OR 2.578), whereas the TST was not. The positive TSPOT rates were 58.9 and 65.7% in the low- and high-risk groups, respectively. The frequency of indeterminate results was higher for the QFT (12.6%) compared with the TSPOT (4.8%). In conclusion, the IGRAs can be useful for the diagnosis of latent TB infection in haemodialysis patients.
128: Veterinary microbiology, 2010 Apr 21, 142(1-2)
Interferon-gamma induction correlates with protection by DNA vaccine expressing E2 glycoprotein against classical swine fever virus infection in domestic pigs.
[Abstract]Classical swine fever (CSF) is a highly contagious viral infection affecting domestic and wild pigs. For classical swine fever virus (CSFV), immunization with plasmids expressing different versions of glycoprotein E2 has proven an effective way to induce protection. Previously, we have also shown that immunization with DNA vaccine expressing glycoprotein E2 (DNA-E2) induced specific T helper cell responses in the absence of neutralizing antibodies. However, the role of T cell responses in protection against CSFV is largely unknown. Here we have extended these studies to deeply characterize the role of T cell responses by a DNA-E2 and their correlation with protection against CSFV infection. Thus, pigs vaccinated with the DNA vaccine induced a strong cellular immune response, characterized by the specific induction IFN-gamma expressing T cells after vaccination without any detectable levels of CSFV neutralizing antibodies. Constant levels of CSFV-specific IFN-gamma producing cells observed from the beginning of the infection until 7 days after challenge in vaccinated animals might contribute to early control of CSFV replication, at least until neutralizing antibodies are developed. Severe clinical signs of the disease, including high titers of viremia, pyrexia and virus spread to different organs, were recorded in the non-vaccinated challenged animals, in comparison to the vaccinated animals where only one animal showed mild clinical signs and a short peak of viremia. Lack of complete protection in this animal correlated with a delay on the induction of neutralizing antibodies, detectable only from day 11 post-CSFV challenge. Conversely, the rest of the pigs within the group developed neutralizing antibodies as early as at day two post-challenge, correlating with sterile protection. Finally, an inverse correlation seemed to exist between early induction of IFN-alpha and the protection observed, while IL-10 seemed to be differentially regulated in vaccinated and non-vaccinated animals. Our results support the relevance of the induction of a strong T cellular response to confer a solid protection upon DNA vaccination against CSFV. Further experiments are needed to be done in order to clarify the key cytokines playing a role in CSFV-protection and to obtain emergency vaccines capable to confer robust and fast protection.
129: Respiratory medicine, 2010 Mar, 104(3)
Serial interferon-gamma release assays after rifampicin prophylaxis in a tuberculosis outbreak.
[Abstract]Even though some studies have reported the results of serial interferon-gamma release assays (IGRAs) during isoniazid prophylactic treatment, serial results have not been reported after rifampicin prophylaxis. A contact investigation was conducted after a tuberculosis (TB) outbreak in an accommodation facility. The tuberculin skin test (TST) and the QuantiFERON-TB Gold In-Tube (QFT-GIT) test were performed in 214 contacts with normal chest radiographs. Rifampicin prophylaxis was initiated in TST+/QFT-GIT+ subjects, and the QFT-GIT test was repeated upon completion of 4 months of rifampicin treatment. Among the 214 contacts, the TST and QFT-GIT test results were positive in 67.7% and 56.7%, respectively, and the agreement between the two tests was fair-to-good (78.3%, kappa=0.55, p<0.001). The QFT-GIT test was positive in 77% (97/126) of contacts with positive TST results. Rifampicin prophylaxis was completed in 81 subjects with good compliance. Among 74 subjects with valid serial QFT-GIT test results, IFN-gamma levels decreased in 97.3% (72/74) of the subjects and QFT-GIT test reversion (positive to negative) was achieved in 31 subjects (41.9%). Subjects without QFT-GIT test reversion had a significantly higher baseline TST induration sizes (18.3+/-4.8 vs. 14.9+/-3.4mm, p<0.01) and IFN-gamma levels (18.6+/-17.9 vs. 3.2+/-7.5IU/mL, p<0.01) than the subjects with QFT-GIT test reversion. Thus, IGRAs may be useful in evaluating the therapeutic response to rifampicin prophylaxis in TB contacts. However, considering that this was not a controlled study, a prospective controlled study is needed to determine whether rifampicin prophylaxis truly affects QFT-GIT reversion.
130: The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2009 Nov, 13(11)
Evaluation of an interferon-gamma release assay, T-SPOT.TB, in a population with a low prevalence of tuberculosis.
[Abstract]SETTING: Great Lakes, Illinois, USA. OBJECTIVE: To compare the performance of an interferon-gamma release assay (T-SPOT.TB) and tuberculin skin test (TST) in a population with a low prevalence of tuberculosis (TB) that was predominantly US-born and not bacille Calmette-Gu¨¦rin-vaccinated. DESIGN: A total of 414 subjects with absence of a previous positive TST were enrolled, of whom 326 yielded analyzable results for both TST and T-SPOT.TB. RESULTS: Overall agreement between T-SPOT.TB and TST was 98.2% (95%CI 96.0-99.3). The specificity of T-SPOT.TB in individuals judged to be at low risk for TB infection was 98.9% (95%CI 96.9-99.8). Of 326 subjects, 8 (2.5%) had a positive T-SPOT.TB result, six of which occurred in the absence of a positive TST. Of these, at least three appeared to have risk factors, suggesting the possibility of a false-negative TST result. CONCLUSION: Because of the excellent agreement between the TSPOT.TB and the TST, either test can serve as an effective diagnostic tool in populations at low risk for TB. As the tests have specific advantages and disadvantages, health care providers have leeway in choosing the most appropriate test for the population they are treating.
131: The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2009 Nov, 13(11)
Interferon-gamma release assay test characteristics depend upon the prevalence of active tuberculosis.
[Abstract]BACKGROUND: Tuberculin skin tests (TSTs) may be negative in the absence of latent tuberculosis infection (LTBI) or in the presence of active tuberculosis (TB). The same phenomenon likely holds for interferon-gamma release assays (IGRAs). METHODS: A mathematical model of LTBI test specificity was developed using elementary probability theory. Implications for IGRA study design, and data collection and analysis are presented. RESULTS: The model demonstrates that the specificity of any test for LTBI is theoretically affected by its sensitivity to active TB, and by the distribution of TB, LTBI and healthy controls. Moreover, changing cut-off points to increase the sensitivity for active TB will cause a decline in the specificity for LTBI. Published data are used to demonstrate these counterintuitive results. CONCLUSIONS: As a result of the markedly dissimilar health statuses associated with a negative LTBI test, IGRA specificity for LTBI and sensitivity to active TB depend upon TB and LTBI prevalence. A trade-off exists between the specificity of IGRAs to LTBI and sensitivity to active TB. Field studies of IGRAs will require standardized collection of symptoms of active TB to distinguish LTBI suspects from TB suspects. Different cut-off points for IGRA use in TB suspects and LTBI suspects will likely be needed.
132: Infection and immunity, 2009 Oct 26, 146(5)
Impairment of Interferon-{gamma} Signaling in Human Neutrophils Infected with Anaplasma phagocytophilum.
[Abstract]Anaplasma (A.) phagocytophilum, the causative agent of tick-borne human granulocytic anaplasmosis (HGA), is an intracellular bacterium which survives and multiplies inside polymorphonuclear neutrophil granulocytes (PMN). Increased bacterial burden in IFN-gamma-deficient mice suggested a major role of IFN-gamma in the control of A. phagocytophilum. Here we investigated whether infection of human PMN with A. phagocytophilum impairs IFN-gamma signaling thus facilitating intracellular survival of the bacterium. The secretion of the IFN-gamma-inducible chemokines IP-10/CXCL10 and MIG/CXCL9 was markedly inhibited in infected neutrophils. Molecular analyses revealed that, compared to uninfected PMN, A. phagocytophilum decreased the expression of the IFN-gamma receptor alpha-chain CD119, diminished the IFN-gamma-induced phosphorylation of STAT1, and enhanced the expression of SOCS1 and SOCS3 in PMN. Since IFN-gamma activates various antibacterial effector mechanisms of PMN, the impaired IFN-gamma signaling in infected cells likely contributes to the survival of A. phagocytophilum inside PMN and to HGA disease development.
133: Immunology, 2009 Oct 21, 146(5)
Eosinophils infiltrate thyroids, but have no apparent role in induction or resolution of experimental autoimmune thyroiditis in interferon-gamma mice.
[Abstract]Summary Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by mouse thyroglobulin (MTg)-sensitized splenocytes activated with MTg and interleukin (IL)-12. Our previous studies showed that, when used as donors and recipients, interferon (IFN)-gamma(-/-) and wild-type (WT) DBA/1 mice both develop severe G-EAT. Thyroid lesions in IFN-gamma(-/-) mice have many eosinophils and few neutrophils, while those in WT mice have extensive neutrophil infiltration and few eosinophils. Thyroid lesions in IFN-gamma(-/-) mice consistently resolve by day 40-50, whereas those in WT mice have ongoing inflammation and fibrosis persisting for more than 60 days. To determine if the extensive infiltration of eosinophils in thyroids of IFN-gamma(-/-) mice contributes to thyroid damage and/or early resolution of G-EAT, anti-IL-5 was used to inhibit migration of eosinophils to thyroids. G-EAT severity was compared at day 20 and day 40-50 in IFN-gamma(-/-) recipients given anti-IL-5 or control immunoglobulin G (IgG). Thyroids of anti-IL-5-treated IFN-gamma(-/-) mice had few eosinophils and more neutrophils at day 20, but G-EAT severity scores were comparable to those of control IgG-treated mice at both day 20 and day 40-50. Expression of chemokine (C-X-C motif) ligand 1 (CXCL1) mRNA was higher and that of chemokine (C-C motif) ligand 11 (CCL11) mRNA was lower in thyroids of anti-IL-5-treated IFN-gamma(-/-) mice. IL-5 neutralization did not influence mRNA expression of most cytokines in IFN-gamma(-/-) mice. Thus, inhibiting eosinophil migration to thyroids did not affect G-EAT severity or resolution in IFN-gamma(-/-) mice, suggesting that eosinophil infiltration of thyroids occurs as a consequence of IFN-gamma deficiency, but these cells have no apparent pathogenic role in G-EAT.
134: Journal of immunology (Baltimore, Md. : 1950), 2009 Oct 19, 146(5)
Responsiveness of Stromal Fibroblasts to Interferon-{gamma} Blocks Tumor Growth Via Angiostasis.
[Abstract]The importance of stromal cells for tumor is akin to soil for seed. However, the interaction among these cells is far from understood. In this study, we show that stromal fibroblasts exist not only during tumor progression but also during regression stage, together with immune effector cells. Coinjection of stromal fibroblasts with tumor cells often promotes tumor growth. However, the presence of IFN-gamma significantly impairs the ability of these cells to promote tumor growth due to a reduced angiogenesis. The mechanism relies mainly on the IFN-gamma-mediated down-regulation of vascular endothelial growth factor production by fibroblasts. The results reveal a novel link between immune cells and nonbone marrow-derived stromal cells, and define stromal fibroblasts as the main targets of IFN-gamma in tumor immunity.
135: Medical mycology : official publication of the International Society for Human and Animal Mycology, 2009 Oct 19, 146(5)
Voriconazole use and pharmacokinetics in combination with interferon-gamma for refractory cryptococcal meningitis in a patient receiving low-dose ritonavir.
[Abstract]We present a case of relapsing cryptococcal meningitis unresponsive to standard therapy. Voriconazole induction, including the utilization of voriconazole therapeutic drug monitoring in both serum and CSF, with transition to voriconazole plus interferon-gamma (IFN-G) was successfully used in a patient receiving antiretroviral therapy with abacavir/ lamivudine and lopinavir/ritonavir. Initial voriconazole levels at standard doses of 4 mg/ kg twice daily intravenously were low when co-administered with lopinavir/ritonavir but increased to recommended therapeutic levels with an increase of the voriconazole dose to 7 mg/kg twice daily. This case highlights the utility of voriconazole therapeutic drug monitoring when prescribed concurrently with a ritonavir boosted protease inhibitor and the potential role of combination therapy with IFN-G for refractory cryptococcal meningitis.
136: Immunity, 2009 Oct 16, 31(4)
Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases.
[Abstract]Interferon-gamma (IFN-gamma) is an important mediator of immunity and inflammation that utilizes the JAK-STAT signaling pathway to activate the STAT1 transcription factor. Many functions of IFN-gamma have been ascribed to direct STAT1-mediated induction of immune effector genes, but recently it has become clear that key IFN-gamma functions are mediated by cross-regulation of cellular responses to other cytokines and inflammatory factors. Here, we review mechanisms by which IFN-gamma and STAT1 regulate signaling by Toll-like receptors, inflammatory factors, tissue-destructive cytokines, anti-inflammatory cytokines, and cytokines that activate opposing STATs. These signaling mechanisms reveal insights about how IFN-gamma regulates macrophage activation, inflammation, tissue remodeling, and helper and regulatory T cell differentiation and how Th1 and Th17 cell responses are integrated in autoimmune diseases.
137: Clinical cancer research : an official journal of the American Association for Cancer Research, 2009 Oct 13, 200(8)
Interferon-{gamma}-Dependent Infiltration of Human T Cells into Neuroblastoma Tumors In vivo.
[Abstract]PURPOSE: To investigate the impact of interferon-gamma-mediated upregulation of major histocompatibility complex class I expression on tumor-specific T-cell cytotoxicity and T-cell trafficking into neuroblastoma tumors in vivo. EXPERIMENTAL DESIGN: Restoration of major histocompatibility complex class I expression by interferon-gamma treatment enhances killing of neuroblastoma cells. To understand the potential of this approach in vivo, we developed a novel model of neuroblastoma in which NOD/scid/IL2Rgamma(null) immunodeficient mice are engrafted with both human T cells and tumor cells. RESULTS: Here, we show enhanced killing of neuroblastoma cells by patient-derived, tumor-specific T cells in vitro. In addition, interferon-gamma treatment in vivo induces efficient upregulation of major histocompatibility complex class I expression on neuroblastoma tumor cells, and this is accompanied by significantly enhanced infiltration of T cells into the tumor. In a pilot clinical trial in patients with high-risk neuroblastoma, we similarly observed augmented T-cell trafficking into neuroblastoma nests in tumor biopsy specimens obtained from patients after 5 days of systemic interferon-gamma therapy. CONCLUSIONS: Interferon-gamma overcomes critical obstacles to the killing of human neuroblastoma cells by specific T cells. Together, these findings provide a rationale for the further testing of interferon-gamma as an approach for improving the efficacy of T cell-based therapies for neuroblastoma and other major histocompatibility complex class I-deficient malignancies. In addition, we describe a model that may expedite the preclinical screening of approaches aimed at augmenting T-cell trafficking into human tumors. (Clin Cancer Res 2009;15(21):OF1-7).
138: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2009 Nov, 15(11)
Dichotomous role of interferon-gamma in allogeneic bone marrow transplant.
[Abstract]Interferon (IFN)-gamma is a pleiotropic cytokine with a central role in innate and adaptive immunity. As a potent pro-inflammatory and antitumor cytokine, IFN-gamma is conventionally thought to be responsible for driving cellular immune response. On the other hand, accumulating evidence suggests that IFN-gamma also has immunosuppressive activity. An important role for IFN-gamma in inhibiting graft-versus-host disease (GVHD) has been demonstrated in murine models, despite IFN-gamma being one of the key factors amplifying T cell activation during the process of acute GVHD (aGVHD), the major complication and cause of post-transplant mortality in allogeneic bone marrow transplantation (BMT). At the same time, IFN-gamma facilitates graft-versus-leukemia (GVL) activity. Dissociation of GVL effects from GVHD has been the ultimate goal of allogeneic BMT in the treatment of hematologic malignancies. This paradoxic role of IFN-gamma makes modulating its activity a promising strategy to maximize GVL while minimizing GVHD and improve clinical outcomes in BMT. In this review, the effects of IFN-gamma on GVHD and GVL are discussed with consideration of the mechanism of IFN-gamma action.
139: Hepatology (Baltimore, Md.), 2009 Dec, 50(6)
Mechanistic insights into immunomodulation by hepatic stellate cells in mice: A critical role of interferon-gamma signaling.
[Abstract]The liver is considered to be an immune-privileged organ that favors the induction of tolerance. The underlying mechanisms are not completely understood. Interestingly, liver transplants are spontaneously accepted in several animal models, but hepatocyte transplants are acutely rejected, suggesting that liver nonparenchymal cells may effectively protect the parenchymal cells from immune attack. We have shown the profound T cell inhibitory activity of hepatic stellate cells (HSCs). Thus, cotransplantation with HSCs effectively protects islet allografts from rejection in mice. In this study, using T cell receptor transgenic and gene knockout approaches, we provided definitive evidence that HSCs protected cotransplanted islet allografts by exerting comprehensive inhibitory effects on T cells, including apoptotic death in graft-infiltrating antigen-specific effector T cells and marked expansion of CD4(+) Forkhead box protein (Foxp)3(+) T regulatory (Treg) cells. All these effects required an intact interferon-gamma (IFN-gamma) signaling in HSCs, demonstrated by using HSCs isolated from IFN-gamma receptor 1 knockout mice. B7-H1 expression on HSCs, a product molecule of IFN-gamma signaling, was responsible for induction of T cells apoptosis, but had no effect on expansion of Treg cells, suggesting that undetermined effector molecules produced by IFN-gamma signaling is involved in this process. Conclusion: Upon inflammatory stimulation, specific organ stromal cells (such as HSCs in the liver) demonstrate potent immune regulatory activity. Understanding of the mechanisms involved may lead to development of novel strategies for clinical applications in transplantation and autoimmune diseases. (HEPATOLOGY 2009.).
140: The Journal of infection, 2009 Dec, 59(6)
Diagnostic performance of an enzyme-linked immunospot assay for interferon-gamma in extrapulmonary tuberculosis varies between different sites of disease.
[Abstract]Objectives: To evaluate diagnostic performance of an enzyme-linked immunospot assay for interferon-gamma (T SPOT-TB) in patients with suspected extrapulmonary tuberculosis (TB). Methods: From January 2007 to December 2008, patients with suspected extrapulmonary TB were prospectively enrolled from 2 tertiary care hospitals. Results: A total of 138 patients with suspected extrapulmonary TB were enrolled; 50 patients had positive culture for Mycobacterium tuberculosis and 39 patients had probable TB. The sites of infection were lymph node (n=20), pleura (n=19), bone/joint (n=15), urinary tract (n=7), peritoneum (n=7), meninges (n=6), disseminated (n=5), intestine (n=3), pericardium (n=2), skin (n=2), throat (n=1), neck (n=1), and genitalia (n=1). The overall sensitivity and specificity were 79.8% (71/89) and 81.6% (40/49). The sensitivity ranged from 100% for tuberculous meningitis, tuberculous pericarditis, and intestinal TB, 95% for lymphadenitis, to 42.9% for tuberculous peritonitis. The sensitivity of the T SPOT-TB assay was 70.6% in immunocompromised patients and 85.5% in immunocompetent patients (p=0.09). Conclusions: The T SPOT-TB assay can be a useful tool for diagnosing extra-pulmonary TB in immunocompetent and immunocompromised patients, particularly for tuberculous meningitis, pericarditis, lymphadenitis, and intestinal TB.
141: Journal of immunological methods, 2009 Dec 31, 351(1-2)
Interferon-gamma release assay: a simple method for detection of varicella-zoster virus-specific cell-mediated immunity.
[Abstract]Herpes zoster is closely related to decreased varicella-zoster virus (VZV)-specific cell-mediated immunity. We validated a new assay for measuring VZV-specific immunity. We cultured the whole blood of healthy subjects with live attenuated VZV vaccine. Cultured supernatants were harvested at 24-h intervals and assayed for interferon-gamma (IFN-gamma) by an enzyme-linked immunosorbent assay (ELISA). The 48-h culture was suitable for estimating IFN-gamma release. IFN-gamma production was stable after standing for at least 4h at room temperature. IFN-gamma production was observed in whole blood from subjects with recent VZV infection, but not in blood from subjects na?ve to the virus. Thus, the IFN-gamma release assay may be useful as a new surrogate assay for measuring VZV-specific immunity.
142: Immunity, 2009 Oct 16, 31(4)
CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-gamma locus.
[Abstract]How cell type-specific differences in chromatin conformation are achieved and their contribution to gene expression are incompletely understood. Here we identify a cryptic upstream orchestrator of interferon-gamma (IFNG) transcription, which is embedded within the human IL26 gene, compromised of a single CCCTC-binding factor (CTCF) binding site and retained in all mammals, even surviving near-complete evolutionary deletion of the equivalent gene encoding IL-26 in rodents. CTCF and cohesins occupy this element in vivo in a cell type-nonspecific manner. This element is juxtaposed to two other sites located within the first intron and downstream of Ifng, where CTCF, cohesins, and the transcription factor T-bet bind in a T helper 1 (Th1) cell-specific manner. These interactions, close proximity of other elements within the locus to each other and to the gene encoding interferon-gamma, and robust murine Ifng expression are dependent on CTCF and T-bet. The results demonstrate that cooperation between architectural (CTCF) and transcriptional enhancing (T-bet) factors and the elements to which they bind is required for proper Th1 cell-specific expression of Ifng.
143: Brain, behavior, and immunity, 2010 Feb, 24(2)
A direct cross-talk between interferon-gamma and sonic hedgehog signaling that leads to the proliferation of neuronal precursor cells.
[Abstract]Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that is critical for innate and adaptive immunity. Recent evidence suggests a connection between IFN-gamma signaling and the sonic hedgehog (Shh) pathway in the developing brain with CNS-targeted expression of IFN-gamma transgene in mice. To determine the relationship between these distinct pathways, we have found that IFN-gamma induces a rapid Shh transcription in cultured primary granular neuron precursor (GNP) cells. The transcriptional induction of Shh by IFN-gamma is resistant to protein synthesis inhibition. Chromatin immunoprecipitation (ChIP) analysis reveals a direct binding of signal transducer and activator of transcription (STAT) 1 to the Shh promoter. Functional analyses, including dual immunofluorescent labeling with 5-bromodeoxyuridine (BrdU) incorporation indicate that IFN-gamma treatment leads to significant GNP proliferation. This mitogenic effect of IFN-gamma is blocked by inhibition of Shh signaling. Therefore, Shh is an IFN-gamma target gene and is responsible for IFN-gamma-induced GNP proliferation. This previously unrecognized cross-talk between IFN-gamma and Shh highlights a potential importance of this immune mediator in the pathogenesis of human developmental and psychiatric disorders.
144: Circulation research, 2009 Nov 6, 105(10)
Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction.
[Abstract]RATIONALE: Interferon-gamma-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response. OBJECTIVE: To study the role of IP-10 in cardiac repair and remodeling. METHODS AND RESULTS: We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10(-/-) hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10(-/-) infarcts had more intense infiltration with CD45(+) leukocytes, Mac-2(+) macrophages, and alpha-smooth muscle actin (alpha-SMA)(+) myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and alpha-SMA(+) cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices. CONCLUSIONS: Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.
145: Cellular signalling, 2010 Jan, 22(1)
Mathematical modelling of interferon-gamma signalling in pancreatic stellate cells reflects and predicts the dynamics of STAT1 pathway activity.
[Abstract]Signal transducer and activator of transcription (STAT) 1 is essentially involved in the mediation of antifibrotic interferon-gamma (IFNgamma) effects in pancreatic stellate cells (PSC). Here, we have further analysed the activation of the STAT1 pathway in a PSC line by combining quantitative data generation with mathematical modelling. At saturating concentrations of IFNgamma, a triphasic pattern of STAT1 activation was observed. An initial, rapid induction of phospho-STAT1 was followed by a plateau phase and another, long-lasting phase of further increase. The late increase occurred despite enhanced expression of the feedback inhibitor (SOCS1), and corresponded to increased levels of total STAT1 protein. If IFNgamma was applied at non-saturating concentrations, phospho-STAT1 and SOCS1 levels peaked and declined again over a 12hour period, while STAT1 protein levels remained high. The mathematical model, based on a system of ordinary differential equations, describes temporal changes of the network components as a function of interactions and transport processes. The model reproduced activation profiles of all components of the STAT1 pathway that were experimentally analysed. Furthermore, it successfully predicted the dynamics of network components in additional experimental studies. Based on experimental findings and the results obtained from modelling, we suggest exhaustion of applied IFNgamma and STAT1 dephosphorylation by tyrosine phosphatases as limiting factors of STAT1 activation in PSC. In contrast, we did not obtain compelling evidence that SOCS1 acts as an efficient feedback inhibitor in our experimental system. We believe that further investigations into mathematical modelling of the STAT1 pathway will improve the understanding of the antifibrotic interferon action.
146: The Journal of infectious diseases, 2009 Nov 1, 200(9)
The HLA-E(R)/HLA-E(R) Genotype Affects the Natural Course of Hepatitis C Virus (HCV) Infection and Is Associated with HLA-E-Restricted Recognition of an HCV-Derived Peptide by Interferon-gamma-Secreting Human CD8(+) T Cells.
[Abstract]Recently, we showed chronic hepatitis C to be associated with increased expression of HLA-E and identified peptide hepatitis C virus (HCV) core amino acids 35-44 as a ligand for HLA-E that stabilizes HLA-E expression, favoring inhibition of natural killer cell cytotoxicity. Here we describe HLA-E-restricted recognition of peptide HCV core amino acids 35-44 by CD8(+) T cells. Frequency of HLA-E-restricted responses was significantly higher in patients homozygous for the HLA-E(R) allele (60% vs 38%; [Formula: see text]). Moreover, we found that the HLA-E(R) allelic variant confers protection against chronic infection with HCV genotypes 2 and 3. Taken together, our data indicate an important immunomodulating function of HLA-E in hepatitis C.
147: DNA and cell biology, 2010 Jan, 29(1)
Interferon-gamma of the Giant Panda (Ailuropoda melanoleuca): Complementary DNA Cloning, Expression, and Phylogenetic Analysis.
[Abstract]Interferon-gamma (IFN-gamma) is the only member of type II IFN and is vital in the regulation of immune and inflammatory responses. Herein we report the cloning, expression, and sequence analysis of IFN-gamma from the giant panda (Ailuropoda melanoleuca). The open reading frame of this gene is 501 base pair in length and encodes a polypeptide consisting of 166 amino acids. All conserved N-linked glycosylation sites and cysteine residues among carnivores were found in the predicted amino acid sequence of the giant panda. Recombinant giant panda IFN-gamma with a V5 epitope and polyhistidine tag was expressed in HEK293 host cells and confirmed by Western blotting. Phylogenetic analysis of mammalian IFN-gamma-coding sequences indicated that the giant panda IFN-gamma was closest to that of carnivores, then to ungulates and dolphin, and shared a distant relationship with mouse and human. These results represent a first step into the study of IFN-gamma in giant panda.
148: The Journal of biological chemistry, 2009 Nov 13, 284(46)
Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway.
[Abstract]Recent reports demonstrate T-cell infiltration of adipose tissue in early obesity. We hypothesized that interferon (IFN) gamma, a major T-cell inflammatory cytokine, would attenuate human adipocyte functions and sought to establish signaling mechanisms. Differentiated human adipocytes were treated with IFNgamma +/- pharmacological inhibitors prior to insulin stimulation. [(3)H]Glucose uptake and AKT phosphorylation were assessed as markers of insulin sensitivity. IFNgamma induced sustained loss of insulin-stimulated glucose uptake in human adipocytes, coincident with reduced Akt phosphorylation and down-regulation of the insulin receptor, insulin receptor substrate-1, and GLUT4. Loss of adipocyte triglyceride storage was observed with IFNgamma co-incident with reduced expression of peroxisome proliferator-activated receptor gamma, adiponectin, perilipin, fatty acid synthase, and lipoprotein lipase. Treatment with IFNgamma also blocked differentiation of pre-adipocytes to the mature phenotype. IFNgamma-induced robust STAT1 phosphorylation and SOCS1 mRNA expression, with modest, transient STAT3 phosphorylation and SOCS3 induction. Preincubation with a non-selective JAK inhibitor restored glucose uptake and Akt phosphorylation while completely reversing IFNgamma suppression of adipogenic mRNAs and adipocyte differentiation. Specific inhibition of JAK2 or JAK3 failed to block IFNgamma effects suggesting a predominant role for JAK1-STAT1. We demonstrate that IFNgamma attenuates insulin sensitivity and suppresses differentiation in human adipocytes, an effect most likely mediated via sustained JAK-STAT1 pathway activation.
149: The Journal of infection, 2009 Dec, 59(6)
False-negative results by enzyme-linked immunospot assay for interferon-gamma among patients with culture-confirmed tuberculosis.
[Abstract]Objectives: To evaluate diagnostic performance of an enzyme-linked immunospot assay for interferon-gamma (T SPOT-TB) in patients with suspected extrapulmonary tuberculosis (TB). Methods: From January 2007 to December 2008, patients with suspected extrapulmonary TB were prospectively enrolled from 2 tertiary care hospitals. Results: A total of 138 patients with suspected extrapulmonary TB were enrolled; 50 patients had positive culture for Mycobacterium tuberculosis and 39 patients had probable TB. The sites of infection were lymph node (n=20), pleura (n=19), bone/joint (n=15), urinary tract (n=7), peritoneum (n=7), meninges (n=6), disseminated (n=5), intestine (n=3), pericardium (n=2), skin (n=2), throat (n=1), neck (n=1), and genitalia (n=1). The overall sensitivity and specificity were 79.8% (71/89) and 81.6% (40/49). The sensitivity ranged from 100% for tuberculous meningitis, tuberculous pericarditis, and intestinal TB, 95% for lymphadenitis, to 42.9% for tuberculous peritonitis. The sensitivity of the T SPOT-TB assay was 70.6% in immunocompromised patients and 85.5% in immunocompetent patients (p=0.09). Conclusions: The T SPOT-TB assay can be a useful tool for diagnosing extra-pulmonary TB in immunocompetent and immunocompromised patients, particularly for tuberculous meningitis, pericarditis, lymphadenitis, and intestinal TB.
150: Immunobiology, 2010 Jun, 215(6)
Interferon-gamma-mediated pathways are induced in human CD34(+) haematopoietic stem cells.
[Abstract]Pro-inflammatory cytokines like interferon-gamma (IFN-gamma) are considered to be important in the development of anaemia of chronic disease (ACD). Both, inhibitory and stimulatory activities of IFN-gamma on erythropoiesis have been observed in vitro earlier. IFN-gamma induces several biochemical pathways in human monocytes, among them neopterin formation by GTP-cyclohydrolase I (GTP-CH I) and tryptophan degradation by the enzyme indoleamine 2,3-dioxygenase (IDO). IDO-mediated tryptophan deprivation efficiently inhibits the growth of proliferating cells and microbes, thus we wanted to examine whether enhanced tryptophan degradation by monocytic precursor cells also suppresses erythropoiesis. Therefore, IFN-gamma-mediated pathways were investigated in human CD34(+) progenitor cells, and effects of IFN-gamma on the proliferative activity of different progenitor subpopulations were studied. Cells were either cultivated in agar-conditioned medium (ACM) or in medium containing erythroid growth factors interleukin-3 (IL-3) and stem cell factor (SCF; EGFCM). Stimulation of CD34(+) cells with IFN-gamma in different doses (either 5000U/ml once or 200 and 400U/ml every other day) induced tryptophan degradation and in parallel also neopterin formation. Unstimulated cells cultured with ACM produced higher amounts of neopterin and kynurenine (all p<0.05). IFN-gamma stimulated higher kynurenine and neopterin formation in cells cultivated in EGFCM, stimulation with 400U IFN-gamma every other day was most effective. IFN-gamma stimulated the growth and proliferation of CFU-E and BFU-E (3-8) in both media. In conclusion, stimulation of haematopoietic stem cells with IFN-gamma activates IDO and neopterin formation, and it also exerts an influence on the proliferation of various stem cell populations.
151: Cancer immunology, immunotherapy : CII, 2010 Mar, 59(3)
Natural killer cell is a major producer of interferon gamma that is critical for the IL-12-induced anti-tumor effect in mice.
[Abstract]Although the anti-tumor effect of IL-12 is mediated mostly by IFNgamma, which cell types most efficiently produce IFNgamma and therefore initiate or promote the anti-tumor effect of IL-12 has not been clearly determined. In the present study, we demonstrated hydrodynamic injection of the IL-12 gene led to prolonged IFNgamma production, NK-cell activation and complete inhibition of liver metastasis of CT-26 colon cancer cells in wild-type mice, but not in IFNgamma knockout mice. NK cells expressed higher levels of STAT4 and upon IL-12 administration displayed stronger STAT4 phosphorylation and IFNgamma production than non-NK cells. Adoptive transfer of wild-type NK cells into IFNgamma knockout mice restored IL-12-induced IFNgamma production, NK-cell activation and anti-tumor effect, whereas transfer of the same number of wild-type non-NK cells did not. In conclusion, NK cells are predominant producers of IFNgamma that is critical for IL-12 anti-tumor therapy.
152: Surgery, 2009 Nov, 146(5)
Interferon-gamma 874A>T genetic polymorphism is associated with infectious complications following surgery in patients with thoracic esophageal cancer.
[Abstract]BACKGROUND: Cytokines play a major role in the organization of orchestrated responses to infections, and there is an emerging consensus that cytokine gene polymorphisms mediate individual variations in cytokine expression. Our aim in this study was to assess whether cytokine polymorphisms were associated with infectious complications following esophagectomy in a Japanese population. METHODS: The study participants were Japanese patients treated with transthoracic esophagectomy without neoadjuvant treatment. DNA was extracted from blood samples, and genetic polymorphisms for interferon (INF)-gamma, tumor necrosis factor-alpha and -beta, transforming growth factor-beta1, interleukin (IL)-1beta, IL-1 receptor antagonist, IL-2, IL-6, IL-6 receptor, IL-10, and IL-12beta were investigated using the polymerase chain reaction-restriction fragment length polymorphism method. We then assessed the association between gene polymorphisms and postoperative infection. RESULTS: Of the 110 patients studied, 18 (16%) developed a postoperative infection (pneumonia, 14 patients; pyothorax, 5; intraabdominal abscess, 1; neck abscess, 1; sepsis, 2). Although the characteristics of patients who developed postoperative infections did not differ, analysis of the genotypes using the Fisher exact test revealed a significantly (P = .0215) greater incidence of postoperative infections among those carrying the INF-gamma 874 (rs2430561) A/A and A/T genotypes. Moreover, univariate and multivariate logistic regression models showed patients carrying the INF-gamma 874A/T genotype were significantly more likely to develop postoperative infectious complications (odds ratio>3.4). CONCLUSION: Our findings suggest that the IFN-gamma 874A>T polymorphism is potentially predictive of the likelihood that patients undergoing esophagectomy for thoracic esophageal cancer will develop postoperative infections. This polymorphism may therefore have important clinical relevance and should be considered when treatment regimens are designed.
153: Clinical biochemistry, 2009 Nov, 42(16-17)
Discrepancy between the tuberculin skin test and the levels of serum interferon-gamma in the diagnosis of tubercular infection in contacts.
[Abstract]OBJECTIVE: Our aim was to compare the tuberculin skin test (TST) results and the level of serum IFN-gamma in the diagnosis of TB infection among contact of smear positive tuberculosis. DESIGN AND METHODS: Chest x ray, tuberculin skin test and serum level of interferon-gamma (IFN-gamma) by ELISA were performed to 30 sputum positive tuberculosis patients, their 118 household contacts and 31 healthy controls. RESULTS: The serum level of IFN-gamma was significantly elevated in index cases than in contacts and control groups. There was no statically significant difference in serum level of IFN-gamma between vaccinated and unvaccinated contacts. There was no significant correlation between IFN-gamma level and tuberculin reaction or induration diameter in vaccinated contacts. There was significant correlation between IFN-gamma level and tuberculin reaction or induration diameter in BCG unvaccinated contacts. CONCLUSION: The serum IFN-gamma is a better indicator of the risk of mycobacterial infection than TST in BCG-vaccinated contacts.
154: Vaccine, 2009 Nov 5, 27(47)
Adoptive transfer of protective immunity from Cryptosporidium parvum-infected interferon-gamma and interleukin-12-deficient mice to naive recipients.
[Abstract]We investigated the possibility of transfer immunity from Cryptosporidium parvum-infected interferon-gamma (GKO) and interleukin-12p40 (IL-12KO) deficient C57BL/6 mice to naive mice by transfer of intraepithelial lymphocytes (IELs) and CD4(+) T cells from spleen and mesenteric lymph nodes (MLNs). Three days after the transfer recipients were infected with C. parvum. IELs isolated from GKO donor mice after resolution of infection (day 15) but not at the peak of infection (day 8) significantly reduced the parasite load in recipient mice. In IL-12KO mice, IELs and also CD4(+) T cells isolated from the spleen and MLNs of donor mice at the peak of infection (day 5) and after resolution (day 15) significantly reduced the parasite excretion, emphasizing the role of interferon-gamma in the host-parasite interaction. However, after resolution of infection, interferon-gamma-independent mechanisms have evolved that render GKO IELs capable of protecting mice from severe infection.
155: Cancer science, 2009 Nov, 100(11)
Delayed growth of EL4 lymphoma in SR-A-deficient mice is due to upregulation of nitric oxide and interferon-gamma production by tumor-associated macrophages.
[Abstract]Class A scavenger receptors (SR-A, CD204) are highly expressed in tumor-associated macrophages (TAM). To investigate the function of SR-A in TAM, wild-type and SR-A-deficient (SR-A(-/-)) mice were injected with EL4 cells. Although these groups of mice did not differ in the numbers of infiltrating macrophages and lymphocytes and in neovascularization, SR-A(-/-) mice had delayed growth of EL4 tumors. Expression of inducible nitric oxide (NO) synthase and interferon (IFN)-gamma mRNA increased significantly in tumor tissues from SR-A(-/-) mice. Engulfment of necrotic EL4 cells induced upregulation of NO and IFN-gamma production by cultured macrophages, and production of NO and IFN-gamma increased in SR-A(-/-) macrophages in vitro. IFN-beta production by cultured macrophages was also elevated in SR-A(-/-) macrophages in vitro. These results suggested that the antitumor activity of macrophages increased in SR-A(-/-) mice because of upregulation of NO and IFN-gamma production. These data indicate an important role of SR-A in regulating TAM function by inhibiting toll-like receptor (TLR)4-IFN-beta signaling.
156: Cytokine, 2009 Dec, 48(3)
Interferon-gamma and interleukin-4 single nucleotide gene polymorphisms in Paracoccidioidomycosis.
[Abstract]The gene polymorphisms interferon-gamma (IFN-gamma) +874 T/A and interleukin (IL)-4 -590 C/T have been associated with the altered production of cytokines. Therefore, they might be indicative of the occurrence of Paracoccidioidomycosis (PCM) caused by Paracoccidioides brasiliensis. The analysis of single nucleotide polymorphism (SNP) at position+874 IFN-gamma showed an increase occurrence of A/T genotype in both PCM patients and healthy individuals as control (HIC) (56% and 45%, respectively), while the allelic distribution showed 82% of A allele in the patients and 80% in the controls. The SNP of -590 IL-4 showed that C/T genotype was significantly (p<0.05) more prevalent (39%) in PCM group compared to the HIC group (19%), while IL-4 C/C genotype was significantly less frequent (59%) in the patient group compared to the control group (81%). Otherwise, 41% of PCM patients and 19% of HIC individuals carried the IL-4 T allele. Stimulation of peripheral blood mononuclear cells (PBMC) from PCM patients with cell extract antigenic preparations (PbAg) as well as secreted and surface antigens (MEXO) of P. brasiliensis evidenced that there is no difference in the IFN-gamma production related to A and T alleles between PCM and HIC individuals. However, with IL-4 production, PCM patients classified as C phenotype showed two times more IL-4 production than PCM patients classified as T phenotype and HIC controls. In conclusion, our results suggest that functional genetic variants in the IL-4 promoter could influence the production of IL-4 in PCM.
157: BJOG : an international journal of obstetrics and gynaecology, 2009 Nov, 116(12)
Association of interferon-gamma +874A polymorphism with the risk of developing cervical cancer in north-Indian population.
[Abstract]OBJECTIVE: Interferon gamma (IFN-gamma) is a pro-inflammatory cytokine playing a pivotal role in both innate and adaptive immune responses. A single nucleotide polymorphism located in the first intron of the human IFN-gamma gene can influence the secretion of cytokine. Therefore, we aimed to investigate the association of IFN-gamma T/A gene polymorphism with the risk of cervical cancer. DESIGN: Case-control study. SETTING: Uttar Pradesh State in India. SAMPLE: Two hundred cases with histologically proven cancer of the cervix and healthy controls (n = 230), age and ethnicity matched were recruited in this study. METHODS: Genotyping was performed for bi-allelic +874 (T/A) polymorphism of IFN-gamma by amplification refractory mutation system method. MAIN OUTCOME MEASURES: Low producer IFN-gamma +874 AA genotype was associated with high risk for cervical cancer, which further modulated the increased risk in tobacco users. RESULTS: IFN-gamma AA genotype which is low producer of IFN-gamma was associated with increased risk of cervical cancer (OR = 2.43, P = 0.003). Allele A was at 1.54-fold increased risk of cervical cancer (OR=1.54, P = 0.002). The AA genotype showed statistically significant risk with high stage (III + IV) of cervical cancer (OR = 4.99, P = 0.001). In tobacco users, AA genotype showed significantly increased susceptibility to cervical cancer (OR = 5.08, P = 0.010). CONCLUSION: Variation in IFN-gamma +874 AA genotype because of ethnicity in north-Indian population may represent an important susceptibility biomarker for cervical cancer risk as well as other diseases and should be explored further.
158: Clinical immunology (Orlando, Fla.), 2009 Nov, 133(2)
High sensitivity cytokine detection in acute coronary syndrome reveals up-regulation of Interferon Gamma and Interleukin-10 post Myocardial Infarction.
[Abstract]Inflammation is an important element in the development and destabilization of atherosclerotic plaque. Using a high sensitivity multiplex assay, previously untested in the context of atherosclerotic disease, we determined serum concentrations of GM-CSF, IFNgamma, IL-1beta, IL-2, IL-10, IL-12p70, TNF alpha, IL-6, and IL-8 in 48 Myocardial Infarction (MI) patients, 14 Unstable Angina (UA) patients and 12 healthy controls. IFNgamma levels were significantly higher in MI compared to UA (p=0.0091) and Control groups (p=0.0014). IL-10 also showed higher expression levels between MI, UA groups and Controls (p=0.0299).This up-regulation may reflect the extent of plaque instability and/or rupture in MI patients.Our observations provide evidence that IFNgamma and IL-10 merit further investigation in atherosclerotic disease states as potential markers of disease and therapeutic targets.
159: Phytotherapy research : PTR, 2010 Mar, 24(3)
Antiinflammatory effects of a red orange extract in human keratinocytes treated with interferon-gamma and histamine.
[Abstract]Red oranges are an important component of the so-called Mediterranean diet and they have been used by traditional medicine for their health protective properties, particularly to heal sore throat and cough, suggesting an interesting antiinflammatory activity. The purpose of this study was to evaluate the antiinflammatory activity of a red orange (Citrus sinensis varieties: Moro, Tarocco, Sanguinello) complex (ROC), characterized by high levels of anthocyanins, flavanones, hydroxycinnamic acids and ascorbic acid, on the human keratinocyte line NCTC 2544 exposed to interferon-gamma (IFN-gamma) and histamine. The expression of immunomodulatory membrane molecules such as inter-cellular adhesion molecule-1 (ICAM-1) by Western blot analysis, and the release of chemokines such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) through ELISA kits, were determined. ICAM-1 modulates the permanence and activation of T lymphocytes in the epidermis. MCP-1 is a specific chemoattractant for monocytes and dendritic cells. IL-8 is important for the recruitment of both neutrophils and T lymphocytes. Addition of ROC at different concentrations together with IFN-gamma and histamine induced a dose-dependent inhibition of ICAM-1 expression and MCP-1 and IL-8 release. ROC shows interesting antiinflammatory properties in human keratinocyte cells NCTC 2544. This natural complex could have a topical employment and mitigate the consequences of some skin pathologies. Copyright (c) 2009 John Wiley & Sons, Ltd.
160: The Journal of biological chemistry, 2009 Oct 9, 284(41)
AMP-activated protein kinase mediates the interferon-gamma-induced decrease in intestinal epithelial barrier function.
[Abstract]Impaired epithelial barrier function plays a crucial role in the pathogenesis of inflammatory bowel disease. Elevated levels of the pro-inflammatory cytokine, interferon-gamma (IFNgamma), are believed to be prominently involved in the pathogenesis of Crohn disease. Treatment of T(84) intestinal epithelial cells with IFNgamma severely impairs their barrier properties measured as transepithelial electrical resistance (TER) or permeability and reduces the expression of tight junction proteins such as occludin and zonula occludens-1 (ZO-1). However, little is known about the signaling events that are involved. The cellular energy sensor, AMP-activated protein kinase (AMPK), is activated in response to cellular stress, as occurs during inflammation. The aim of this study was to investigate a possible role for AMPK in mediating IFNgamma-induced effects on the intestinal epithelial barrier. We found that IFNgamma activates AMPK by phosphorylation, independent of intracellular energy levels. Inhibition of AMPK prevents, at least in part, the IFNgamma-induced decrease in TER. Furthermore, AMPK knockdown prevented the increased epithelial permeability, the decreased TER, and the decrease in occludin and ZO-1 caused by IFNgamma treatment of T(84) cells. However, AMPK activity alone was not sufficient to cause alterations in epithelial barrier function. These data show a novel role for AMPK, in concert with other signals induced by IFNgamma, in mediating reduced epithelial barrier function in a cell model of chronic intestinal inflammation. These findings may implicate AMPK in the pathogenesis of chronic intestinal inflammatory conditions, such as inflammatory bowel disease.
161: Biotechnology letters, 2009 Nov, 31(11)
Murine interferon-gamma inducible protein-10 (IP-10) secreted by Lactococcus lactis chemo-attracts human CD3+ lymphocytes.
[Abstract]Chemokines are members of the super family of cytokines necessary for leukocyte recruitment in tissues and lymphoid organs. The interferon-gamma inducible protein-10 (IP-10) chemo-attracts CXCR3-expressing cells, such as activated T lymphocytes and monocytes. We have genetically engineered a strain of Lactococcus lactis to secrete a biologically active murine IP-10 that interacts with human CXCR3, its homolog receptor, and chemo-attracts human CD3+ T lymphocytes.
162: Journal of biomedical materials research. Part A, 2010 May, 93(2)
Functional immobilization of interferon-gamma induces neuronal differentiation of neural stem cells.
[Abstract]Stem cell transplantation provides significant promise to regenerative strategies after injury in the central nervous system. Neural stem/progenitor cells (NSPCs) have been studied in terms of their regenerative capacity and their ability to differentiate into neurons when exposed to various soluble factors. In this study, interferon-gamma (IFN-gamma) was compared with brain-derived neurotrophic factor (BDNF) and erythropoietin and was shown to be the best single growth factor for inducing neuronal differentiation from adult rat brain-derived NSPCs. Next, IFN-gamma was surface immobilized to a methacrylamide chitosan (MAC) scaffold that was specifically designed to match the modulus of brain tissue and neuronal differentiation of NSPCs was examined in vitro by immunohistochemistry. Bioactive IFN-gamma was successfully immobilized and quantified by ELISA. Both soluble and immobilized IFN-gamma on MAC surfaces showed dose dependent neuronal differentiation with soluble saturation occurring at 100 ng/mL and the most effective immobilized IFN-gamma dose at 37.5 ng/cm(2), where significantly more neurons resulted compared with controls including soluble IFN-gamma. (c) 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.
163: Brain, behavior, and immunity, 2010 Feb, 24(2)
LPS-induced indoleamine 2,3-dioxygenase is regulated in an interferon-gamma-independent manner by a JNK signaling pathway in primary murine microglia.
[Abstract]Inflammation-induced activation of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) causes depressive-like behavior in mice following acute activation of the innate immune system by lipopolysaccharide (LPS). Here we investigated the mechanism of IDO expression induced by LPS in primary cultures of microglia derived from neonatal C57BL/6J mice. LPS (10ng/ml) induced IDO transcripts that peaked at 8h and enzymatic activity at 24h, resulting in an increase in extracellular kynurenine, the catabolic product of IDO-induced tryptophan catabolism. This IDO induction by LPS was accompanied by synthesis and secretion of the proinflammatory cytokines TNFalpha and IL-6, but without detectable IFNgamma expression. To explore the mechanism of LPS-induced IDO expression, microglia were pretreated with the c-Jun-N-terminal kinase (JNK) inhibitor SP600125 for 30min before LPS treatment. We found that SP600125 blocked JNK phosphorylation and significantly decreased IDO expression induced by LPS, which was accompanied by a reduction of LPS-induced expression of TNFalpha and IL-6. Collectively, these data extend to microglia the property that LPS induces IDO expression via an IFNgamma-independent mechanism that depends upon activation of JNK. Inhibition of the JNK pathway may provide a new therapy for inflammatory depression.
164: Glia, 2010 Jan 1, 58(1)
Selective estrogen receptor modulators decrease the production of interleukin-6 and interferon-gamma-inducible protein-10 by astrocytes exposed to inflammatory challenge in vitro.
[Abstract]Expression of proinflammatory molecules by glial cells is involved in the pathophysiological changes associated with chronic neurological diseases. Under pathological conditions, astrocytes release a number of proinflammatory molecules, such as interleukin-6 (IL-6) and interferon-gamma-inducible protein-10 (IP-10). The ovarian hormone estradiol exerts protective effects in the central nervous system that, at least in part, may be mediated by a reduction of local inflammation. This study was designed to assess whether estradiol affects the production of IL-6 and IP-10 by primary cultures of newborn mice astrocytes exposed to lipopolysaccharide (LPS), a bacterial endotoxin known to cause neuroinflammation. In addition, the possible anti-inflammatory effect of several selective estrogen receptor modulators (SERMs) was also assessed. LPS induced an increase in the expression of IL-6 and IP-10 mRNA levels in astrocytes and an increase in IL-6 and IP-10 protein levels in the culture medium. These effects of LPS were impaired by estradiol and by the four SERMs tested in our study: tamoxifen, raloxifene, ospemifene, and bazedoxifene. All SERMs tested showed a similar effect on IL-6 and IP-10 mRNA levels, but raloxifene and ospemifene were more effective than tamoxifen and bazedoxifene in reducing protein levels in LPS-treated cultures. Finally, we report that news SERMs, ospemifene and bazedoxifene, exert anti-inflammatory actions by a mechanism involving classical estrogen receptors and by the inhibition of LPS-induced NFkappaB p65 transactivation. The results suggest that estrogenic compounds may be candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of proinflammatory molecules by astrocytes.
165: Research in veterinary science, 2009 Dec, 87(3)
Effects of a standardized purified dry extract from Echinacea angustifolia on proliferation and interferon gamma secretion of peripheral blood mononuclear cells in dairy heifers.
[Abstract]This study was performed to ascertain whether a standardized extract from Echinacea angustifolia (Polinacea) affects proliferation and interferon gamma (IFN-gamma) secretion in bovine peripheral blood mononuclear cells (PBMC). PBMC from six Holstein heifers were incubated with 0, 6.3, 20, 60, or 180 microg/ml of the tested compound. Proliferation was stimulated by concanavalin A (ConA) or pokeweed-mitogen (PWM). Secretion of IFN-gamma was stimulated by ConA. All concentrations of Polinacea exerted a mitogenic effect. With respect to control PBMC (0 microg/ml), the lowest and highest increase of proliferation were observed with Polinacea at 6.3 (2-fold increase) or 180 (10-fold increase) microg/ml, respectively. Polinacea at 180 microg/ml reduced ConA-driven proliferation, whereas at 20 and 60 microg/ml improved proliferation of PWM-stimulated PBMC. IFN-gamma secretion was not affected. In conclusion, Polinacea modulates bovine PBMC proliferation, and deserves to be tested in vivo to define conditions that may benefit from its utilization.
166: The international journal of biochemistry & cell biology, 2009 Nov, 41(11)
Macrophage responses to interferon-gamma are dependent on cystatin C levels.
[Abstract]The aim of the present investigation was to elucidate possible effects of cystatin C on inflammatory responses mediated by macrophages. Previously it has been shown that in vitro treatment of murine peritoneal macrophages with interferon-gamma (IFN-gamma) causes a down-regulation of cystatin C secretion. To investigate whether such changes in cystatin C expression in turn can affect inflammatory responses mediated by macrophages, we have compared effects of IFN-gamma on macrophages isolated from wild-type (cysC(+/+)) and cystatin C knockout (cysC(-/-)) mice. It was shown that IFN-gamma-primed cysC(-/-) macrophages exhibit significantly higher interleukin-10 (IL-10) but lower tumor necrosis factor-alpha (TNF-alpha) expression, and reduced nuclear factor (NF)-kappaB p65 activation, compared to similarly primed cysC(+/+) cells. Exogenously added cystatin C enhanced IFN-gamma-induced activation of NF-kappaB p65 and increased mRNA levels for inducible NO synthase (iNOS) in cysC(-/-) macrophages as well as levels of nitric oxide and TNF-alpha in the cell culture medium, in agreement with an enhanced pro-inflammatory response. Accordingly, IFN-gamma-induced IL-10 mRNA expression in cysC(-/-) macrophages was down-regulated by exogenously added cystatin C. Taken together, our data provide evidence that changes in cystatin C levels alter macrophage responses to IFN-gamma. The latter down-regulates the production of cystatin C, which leads to a suppressed inflammatory condition with enhanced IL-10 levels and down-regulated TNF-alpha and NF-kappaB. It is concluded that cystatin C through this effect can act as an immunomodulatory molecule.
167: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology, 2009 Nov, 34(5)
Utility of quantitative T-cell responses versus unstimulated interferon-{gamma} for the diagnosis of pleural tuberculosis.
[Abstract]The clinical utility of antigen-specific interferon (IFN)-gamma release assays (IGRAs) using pleural mononuclear cells, for the diagnosis of tuberculosis (TB), requires clarification. We compared the diagnostic utility of unstimulated pleural IFN-gamma levels with several pleural antigen-specific T-cell IGRAs (early secretory antigenic target-6 and culture filtrate protein-10 (T-SPOT.(R)TB, QuantiFERON(R)-TB Gold In-tube), purified protein derivative (PPD) and heparin-binding haemagglutinin (HBHA)) in 78 South African TB suspects. Test results were compared against a clinical score and a reference standard. Out of 74 evaluable subjects 48, seven and 19 had definite, probable and no TB, respectively. 11 (15%) out of 74 pleural samples (nine (19%) out of 48 of the definite TB cases) had total cell counts that were inadequate for T-cell processing. In the remaining 63 samples, the sensitivity, specificity, positive predictive value and negative predictive value of different diagnostic methods were as follows. Maximal bioclinical score: 54, 89, 92 and 43%, respectively; T-SPOT.(R)TB: 86, 60, 84 and 64%, respectively; QuantiFERON(R)-TB Gold In-tube: 57, 80, 87 and 44%, respectively; HBHA-specific IGRA: 59, 31, 64 and 27%, respectively; PPD-specific IGRA: 81, 40, 76 and 46%, respectively; and pleural fluid unstimulated IFN-gamma: 97, 100, 100 and 94%, respectively. Unstimulated IFN-gamma was the most accurate test for distinguishing TB from non-TB effusions in a high-burden setting. The antigen-specific T-cell IGRAs were limited by suboptimal accuracy and the inability to isolate sufficient mononuclear cells to perform the assay.
168: Parasitology research, 2009 Mar 3,
Expression of interferon gamma and proinflammatory cytokines in the cecal mucosa of rats experimentally infected with Blastocystis sp. strain RN94-9.
[Abstract]Blastocystis hominis is a zoonotic intestinal protozoan parasite whose pathogenic potential is still controversial. The aim of the present study was to clarify the pathogenicity of Blastocystis parasites in rats. Oral inoculation with 1 x 10(5) cysts of Blastocystis sp. strain RN94-9 in rats resulted in chronic infection in the cecum at least until 4 weeks after infection. Histological examination revealed neither mucosal sloughing nor inflammatory cell infiltration but showed a slight but significant increase in goblet cell numbers in the cecal mucosa 1-3 weeks post-infection. Differential staining of acidic and neutral mucins by the alcian blue-periodic acid-Schiff method showed that the predominantly increased cells were neutral mucin(+) but not acidic mucin(+) goblet cells. Reverse transcription real-time polymerase chain reaction studies demonstrated significant upregulation of the expression of interferon-gamma, interleukin (IL)-12, and tumor necrosis factor alpha, but not IL-6 or granulocyte-macrophage colony-stimulating factor, in the cecal mucosa at 2 and/or 3 weeks post-infection. The induction of local host responses, including mild goblet cell hyperplasia, and significant upregulation of type-1 and proinflammatory cytokines, suggest that Blastocystis sp. strain RN94-9 is a weakly pathogenic organism that could elicit proinflammatory as well as protective responses in local tissues.
169: Circulation, 2009 Mar 2,
Interleukin-17 and Interferon-{gamma} Are Produced Concomitantly by Human Coronary Artery-Infiltrating T Cells and Act Synergistically on Vascular Smooth Muscle Cells.
[Abstract]BACKGROUND: -Atherosclerosis is an inflammatory disease in which interferon (IFN)-gamma, the signature cytokine of Th1 cells, plays a central role. We investigated whether interleukin (IL)-17, the signature cytokine of Th17 cells, is also associated with human coronary atherosclerosis. Methods and Results-Circulating IL-17 and IFN-gamma were detected in a subset of patients with coronary atherosclerosis and in referent outpatients of similar age without cardiac disease but not in young healthy individuals. IL-17 plasma levels correlated closely with those of the IL-12/IFN-gamma/CXCL10 cytokine axis but not with known Th17 inducers such as IL-1beta, IL-6, and IL-23. Both IL-17 and IFN-gamma were produced at higher levels by T cells within cultured atherosclerotic coronary arteries after polyclonal activation than within nondiseased vessels. Combinations of proinflammatory cytokines induced IFN-gamma but not IL-17 secretion. Blockade of IFN-gamma signaling increased IL-17 synthesis, whereas neutralization of IL-17 responses decreased IFN-gamma synthesis; production of both cytokines was inhibited by transforming growth factor-beta1. Approximately 10-fold fewer coronary artery-infiltrating T helper cells were IL-17 producers than IFN-gamma producers, and unexpectedly, IL-17/IFN-gamma double producers were readily detectable within the artery wall. Although IL-17 did not modulate the growth or survival of cultured vascular smooth muscle cells, IL-17 interacted cooperatively with IFN-gamma to enhance IL-6, CXCL8, and CXCL10 secretion. Conclusions-Our findings demonstrate that IL-17 is produced concomitantly with IFN-gamma by coronary artery-infiltrating T cells and that these cytokines act synergistically to induce proinflammatory responses in vascular smooth muscle cells.
170: Cellular & molecular immunology, 2009 Feb, 6(1)
Blockade of Tim-3 Pathway Ameliorates Interferon-gamma Production from Hepatic CD8(+) T Cells in a Mouse Model of Hepatitis B Virus Infection.
[Abstract]T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been reported to participate in the pathogenesis of inflammatory diseases. However, whether Tim-3 is involved in hepatitis B virus (HBV) infection remains unknown. Here, we studied the expression and function of Tim-3 in a hydrodynamics-based mouse model of HBV infection. A significant increase of Tim-3 expression on hepatic T lymphocytes, especially on CD8(+) T cells, was demonstrated in HBV model mice from day 7 to day 18. After Tim-3 knockdown by specific shRNAs, significantly increased IFN-gamma production from hepatic CD8(+) T cells in HBV model mice was observed. Very interestingly, we found Tim-3 expression on CD8(+) T cells was higher in HBV model mice with higher serum anti-HBs production. Moreover, Tim-3 knockdown influenced anti-HBs production in vivo. Collectively, our data suggested that Tim-3 might act as a potent regulator of antiviral T-cell responses in HBV infection.
171: Tissue antigens, 2009 Mar, 73(3)
A structural variant of the human interferon-gamma gene.
[Abstract]The first structural IFNG variant, G54D (c.287G>A, ss105106770), located in the second exon, was identified.
172: Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition, 2008 Nov, 39(6)
[Effects of interferon-gamma on tubular epithelial-myofibroblast transdifferentiation in vitro]
[Abstract]OBJECTIVE: To investigate the effects of interferon-gamma (IFN-gamma) on tubular epithelial-myofibroblast transdifferentiation (TEMT) induced by transforming growth factor (TGF-beta1). METHODS: The normal rat kidney tubular epithelial cells (NRK52E) were cultured and divided into blank (NRK52E cells only) control group, TGF-beta1 (3 ng/mL) treated group, IFN-gamma (1000 IU/mL) treated group, and IFN-gamma inhibition group (TGF-beta1 3 ng/mL + IFN-gamma 200, 400, 600, 1000, 2000, 3000 IU/mL). After 72 hours of treatment, the morphology of cells was observed under phase-contrast microscopy and scanning electron microscopy. The expressions of a-smooth muscle actin (alpha-SMA) and connective tissue growth factor (CTGF) were detected by immunocytochemistry. Flowcytometry was employed to measure the percentage of alpha-SMA+ cells and the mean channel fluorescence (MCF). The expressions of alpha-SMA mRNA and CTGF mRNA were examined by reverse transcription-polymerase chain reaction analyses (RT-PCR). The level of collagen in the culture supernatant was measured by Enzyme-linked immunoadsordent assay (ELISA). RESULTS: NRK52E cells cultured in the control group showed a classic cobblestone morphology. TGF-beta1 induced NRK52E cells to transdifferentiate into myofibroblast-like cells, which showed strong alpha-SMA immunostaining. The TGF-beta1 treated cells had higher percentage of a-SMA+ cells, MCF and alpha-SMA mRNA, increased CTGF mRNA expression, and ascended collagen III than the blank controls (P<0.05). IFN-gamma treated alone did not make any changes to the cell morphology, the expressions of alpha-SMA mRNA and CTGF mRNA and the level of collagen III (P>0.05). IFN-gamma exerted a strong inhibitory effect on the TEMT induced by TGF-beta1. With the increase of IFN-gamma, the percentage of alpha-SMA+ cells, the level of collagen III, and the expressions of alpha-SMA mRNA and CTGF mRNA decreased (P<0.05). CONCLUSION: IFN-gamma inhibits the TEMT induced by TGF-beta1 and reduces the level of collagen III.
173: Annals of the rheumatic diseases, 2010 Jan, 69(1)
Comparison of interferon {gamma} release assays and conventional screening tests before tumour necrosis factor {alpha} blockade in patients with inflammatory arthritis.
[Abstract]OBJECTIVE: To compare the performance of two interferon gamma release assays (IGRAs) and conventional screening tests in patients with inflammatory arthritis undergoing screening for latent tuberculosis infection (LTBI) before treatment with anti-tumour necrosis factor alpha (anti-TNFalpha) compounds. METHODS: Successive patients were subjected to conventional LTBI screening, including a tuberculin skin test (TST). The T-SPOT.TB test was performed on all patients and the QuantiFERON-TB Gold test was performed on a large subset. The results of the IGRAs were compared with the results of conventional screening tests. RESULTS: A total 150 patients were evaluated. The majority (57.9%) had rheumatoid arthritis. Previous vaccination with Bacille Calmette-Guerin was confirmed in 82% of patients. No patient had received prior anti-TB treatment. A total of 57 patients (38.0%) had at least one positive conventional risk factor. In contrast, an unequivocally positive T-SPOT.TB test was seen in only 14/143 (9.8%). There was 98.2% agreement between the two IGRAs. Statistically significant associations were found between each of the IGRAs and both TST and risk history, but not chest x-ray (CXR). A positive IGRA result was significantly associated with increased age. TB was not reactivated in any patient during the follow-up period. Interpretation: This study suggests that IGRAs may be useful when screening for LTBI before anti-TNFalpha therapy in patients with immune-mediated inflammatory diseases. The observations reported here also highlight the inadequate performance of CXR as a marker of LTBI.