interferon beta

C Subfamily
CC Subfamily
CXC Subfamily
CX3C Subfamily

Chemokines

gp130 (IL6ST) shared
IL13RA1 shared
IL3RB (CSF2RB) shared
ILRG shared

interleukin 18
interleukin 18 proprotein
interleukin 1 alpha
interleukin 1, alpha proprotein
interleukin 1 beta
interleukin 1, beta proprotein

interleukin 17
interleukin 17b
interleukin 17E
interleukin 17E isoform 1

IL-1 Family /IL-17 Family

interleukin 10
interleukin 19
interleukin 19 isoform 2
interleukin 20
interleukin 22
interleukin 24
interleukin 24 isoform 1
interleukin 28A
interleukin 28B
interleukin 29

IL-10 Family

interferon alpha family, gene 1
interferon, alpha 1
interferon beta
interferon, beta 1
interferon epsilon 1
interferon, epsilon 1
interferon gamma
interferon, gamma
interferon kappa
interferon, kappa
interferon, omega 1

Interferon Family

CSF1 Egf Flt3l
FLT3LG HGF Kitl
KITLG Pdgfa PDGFB
PDGFC Pdgfd PLEKHQ1
VEGF Vegfa VEGFB
VEGFC

PDGF Family

AMH Bmp2 Bmp7
GDF5 Inhba INHBB
INHBC INHBE Tgfb1
TGFB2 TGFB3

TGF-β Family

CD40LG Eda Fasl
FASLG Lta LTB
TNF Tnfsf10 Tnfsf11
TNFSF12 Tnfsf13 TNFSF13B
Tnfsf14 TNFSF18 TNFSF4
TNFSF7 TNFSF8 TNFSF9

TNF Family

INTERFERON BETA

LATEST LITERATURE

1: Molecules and cells, 2010 Aug 31, 27(9)
p21(WAF1) is involved in interferon-beta- induced attenuation of telomerase activity and human telomerase reverse transcriptase (hTERT) expression in ovarian cancer.

[Abstract]Telomerase activation is a key step in the development of human cancers. Interferon-beta (IFN-beta) signaling induces growth arrest in many tumors but the anticancer mechanism of IFN-beta is poorly understood. In the present study, we show that IFN-beta signaling represses telomerase activity and human telomerase reverse transcriptase (hTERT) transcription in ovarian cancer and suggest that this signaling is mediated by p21(WAF1). IFN-beta triggered down-regulation of telomerase activity and hTERT mRNA expression and also induced p21 expression, independently of p53 induction. Ectopic expression of p21 attenuated hTERT promoter activity. Murine embryonic fibroblasts (MEFs) genetically deficient in p21 (p21-/-) showed elevated (> 15 times) hTERT promoter activity compared to wild-type MEFs. Overexpression of p21 reduced the hTERT promoter activity of p21-/- MEFs and hTERT mRNA expression in HCT119 p21(WAF1) null cell. These findings provide evidence that p21 is a potential mediator of IFN-beta-induced attenuation of telomerase activity and tumor suppression.

2: The Journal of biological chemistry, 2010 Aug 24, 27(9)
Blocking interferon-beta stimulates vascular smooth muscle cell proliferation and arteriogenesis.

[Abstract]Increased interferon (IFN)-beta signaling in patients with insufficient coronary collateralization and an inhibitory effect of IFNbeta on collateral artery growth in mice have been reported. The mechanisms of IFNbeta-induced inhibition of arteriogenesis are unknown. In stimulated monocytes from patients with chronic total coronary artery occlusion and decreased arteriogenic response, whole genome expression analysis showed increased expression of IFNbeta-regulated genes. Immunohistochemically, the IFNbeta receptor was localized in the vascular media of murine collateral arteries. Treatment of vascular smooth muscle cells (VSMC) with IFNbeta resulted in an attenuated proliferation, cell-cycle arrest and increased expression of cyclin-dependent kinase inhibitor-1A (p21). Growth-inhibitory effect of IFNbeta was attenuated by inhibition of p21 by RNA-interference. IFNbeta-treated THP1 monocytes showed enhanced apoptosis. Subsequently, we tested if collateral artery growth can be stimulated by inhibition of IFNbeta-signaling. RNA-interference of the IFNbeta receptor-1 (IFNAR1) increased VSMC proliferation, cell cycle progression, and reduced p21 gene expression. IFNbeta-signaling and FAS and TRAIL expression were attenuated in monocytes from IFNAR1-/- mice, indicating reduced monocyte apoptosis. Hindlimb perfusion restoration one week after femoral artery ligation was improved in IFNAR1-/- mice compared to wildtype mice as assessed by infusion of fluorescent microspheres. These results demonstrate that IFNbeta inhibits collateral artery growth and VSMC proliferation through p21-dependent cell cycle arrest and induction of monocyte apoptosis. Inhibition of IFNbeta stimulates VSMC proliferation and collateral artery growth.

3: Critical care (London, England), 2010 Aug 23, 14(4)
Interferon-beta attenuates lung inflammation following experimental subarachnoid hemorrhage.

[Abstract]ABSTRACT: INTRODUCTION: Aneurysmal subarachnoid hemorrhage (SAH) affects relatively young people and carries a poor prognosis with a case fatality rate of 35%. One of the major systemic complications associated with SAH is acute lung injury (ALI) which occurs in up to one-third of the patients and is associated with poor outcome. ALI in SAH may be predisposed by neurogenic pulmonary oedema (NPE) and inflammatory mediators. The objective of this study was to assess the immunomodulatory effects of interferon-beta (IFN-beta) on inflammatory mediators in the lung after experimental SAH. METHODS: Male Wistar rats were subjected to the induction of SAH by means of the endovascular filament method. Sham-animals underwent sham-surgery. Rats received IFN-beta for 4 consecutive days starting at 2 hours after SAH induction. After 7 days, lungs were analyzed for the expression of inflammatory markers. RESULTS: SAH induced the influx of neutrophils into the lung, and enhanced expression of the pulmonary adhesion molecules E-selectin, inter-cellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 compared to sham-animals. In addition, SAH increased the expression of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-2, and cytokine-induced neutrophil chemoattractant (CINC)-1 in the lung. Finally, TNF-alpha was significantly increased in lungs from SAH-animals compared to sham-animals. IFN-beta effectively abolished the SAH-induced expression of all pro-inflammatory mediators in the lung. CONCLUSIONS: IFN-beta strongly reduces lung inflammation after experimental SAH and may therefore be an effective drug to prevent SAH-mediated lung injury.

4: The Journal of biological chemistry, 2010 Aug 10, 27(9)
Influenza A virus polymerase inhibits type I interferon induction by binding to interferon {beta} promoter stimulator 1.

[Abstract]Type I interferons (IFNs) are known to be critical factors in the activation of host antiviral responses, and are also important in protection from influenza A virus infection. Especially, the RIG-I- and IPS-1-mediated intracellular type I IFN inducing pathway is essential in the activation of antiviral responses in cells infected by influenza A virus. Previously, it has been reported that influenza A virus NS1 is involved in the inhibition of this pathway. We show in this report that the influenza A virus utilizes another critical inhibitory mechanism in this pathway. In fact, the viral polymerase complex exhibited an inhibitory activity on IFNbeta promoter activation mediated by RIG-I and IPS-1, and this activity was not competitive with the function of NS1. Co-immunoprecipitation analysis revealed that each polymerase subunit bound to IPS-1 in mammalian cells, and each subunit inhibited the activation of IFNbeta promoter by IPS-1 independently. In addition, by a combinational expression of each polymerase subunit, IPS-1 induced activation of IFNbeta promoter was more efficiently inhibited by the expression of PB2 or PB2 containing complex. Moreover, the expression of PB2 inhibited the transcription of the endogenous IFNbeta gene induced after influenza A virus infection. These findings demonstrate that the viral polymerase plays an important role for regulating host anti-viral response through the binding to IPS-1 and inhibition of IFNbeta production.

5: Archives of neurology, 2010 Aug, 67(8)
Interferon Beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers.

[Abstract]OBJECTIVE: To describe a patient with neuromyelitis optica (NMO) whose aquaporin 4 (AQP4) antibody levels increased following treatment with interferon beta. DESIGN: Prospective clinical and laboratory case report. SETTING: Institutional referral center for multiple sclerosis (MS). Patient One patient with an initial diagnosis of MS that was later revised to NMO. INTERVENTIONS: A course of interferon beta-1a followed by conventional immunosuppression. Blood samples were collected from the onset of treatment, and clinical and laboratory assessment was performed. MAIN OUTCOME MEASURES: Serum levels of AQP4 antibody and number and characteristics of neurological relapses. RESULTS: After 3 relapses during a 10-month period despite interferon beta-1a treatment, the diagnosis of AQP4 antibody-positive NMO was made and treatment was switched to prednisolone and methotrexate. The AQP4 antibody titers rose dramatically during treatment with interferon beta, and then fell when conventional immunosuppressive therapy was substituted; the patient has remained relapse-free for the subsequent years. CONCLUSIONS: Although previous articles have suggested that interferon beta may increase relapses in NMO, this is the first to illustrate an increase in AQP4 antibodies associated with such treatment.

6: Clinical chemistry and laboratory medicine : CCLM / FESCC, 2010 Aug 3, 112(7)
Transfer of myxovirus-protein-A mRNA assay for interferon-beta bioactivity measurement in multiple sclerosis patients to routine laboratory practice. A 4-year experience.

[Abstract]Abstract Background: As new biomarkers are validated and their significance in the natural history of specific diseases is established, these technologies can be rapidly transferred to clinical application. Since it has been shown that a single post-interferon-beta (IFNbeta) injection measurement of myxovirus-protein-A (MxA) mRNA correlates with IFNbeta bioactivity in IFNbeta treated patients with multiple sclerosis (MS), we had previously validated an assay for its quantification. Methods: We introduced a real-time PCR relative quantification assay into routine clinical practice and measured MxA mRNA expression in 564 samples from 500 unselected IFNbeta treated MS patients over a 4-year period. Results: We confirmed that the assay is reproducible over time, and found that the percentage of patients lacking MxA mRNA induction is comparable to that described in studies performed worldwide after patient selection by pre-screening for the presence of anti-IFNbeta antibodies. Conclusions: In view of its simplicity and reproducibility, this MxA assay is an alternative to anti-IFNbeta antibody determinations for use in routine clinical practice. Clin Chem Lab Med 2010;48.

7: Antiviral research, 2010 Jul 23, 40(8)
Interferon-beta modulates type 1 immunity during influenza virus infection.

[Abstract]Influenza viruses are important human pathogens, associated throughout history with worldwide outbreaks and pandemics. The antiviral effects of interferon (IFN)-alphas?beta against influenza virus infections are well recognized, yet the mechanisms whereby IFNs exert their immunomodulatory effects on an anti-influenza response remain ill-defined. Here, we describe the effects of IFN-beta treatment on the immune response during a respiratory influenza (A/WSN/33) A virus infection of mice. A single dose of IFN-beta (1x10(5) U) enhanced DC migration into the draining lymph node (DLN) on day 3 post-intranasal infection, and subsequently inhibited the migration from the lungs into the DLN of a newly identified late activator antigen presenting cell population associated with type 2 immunity, LAPC. IFN-beta treatment polarized the immune response towards a type 1 immune response, eliciting enhanced T(H)1 effector and cytolytic T cell responses, but diminished T(H)2 effector T cell responses in both the DLN and lung tissues of influenza virus infected mice. Associated with the polarization towards a type 1 immune response, IFN-beta treatment of mice resulted in accelerated viral clearance and diminished pulmonary eosinophilia in infected lung tissues.

8: Multiple sclerosis (Houndmills, Basingstoke, England), 2010 Jul 16, 17(8)
Urinary neopterin and nitric oxide metabolites as markers of interferon {beta}-1a activity in primary progressive multiple sclerosis.

[Abstract]Background: Interferon beta has not been demonstrated to be effective in exploratory phase 2 clinical trials in primary progressive multiple sclerosis. However, using more sensitive indicators of a treatment response, such as biomarkers, might help to identify sub-groups of patients who may benefit from therapy.Objective: To assess the utility of measuring urinary neopterin and nitric oxide metabolite excretion for monitoring interferon beta-1a (IFNbeta-1a) treatment in patients with primary progressive multiple sclerosis.Methods: Fifty patients from a phase II trial of IFNbeta-1a (Placebo n = 20; Avonex(R) 1 x 30 microg/week (IFN-30), n = 15; Avonex(R) 1 x 60 microg/week (IFN-60), n = 15), were enrolled. Patients were assessed using the Expanded Disability Status Scale. Urine samples were collected on each visit, 3 months apart, for a period of 24 months. Nitric oxide metabolites, nitrite/nitrate (NOx), were measured by colorimetric assay and neopterin and creatinine (Cr) were assayed using a high-performance liquid chromatography technique. NOx/creatinine ratio (NOxCR) and urinary neopterin/creatinine ratio (UNCR) quotients were calculated.Results: There was no significant difference between pre-dose, baseline levels of UNCR or NOxCR between the study groups. On the intention-to-treat analysis, there was a significant difference in UNCR levels between the placebo compared with IFN-30 (p = 0.03) or IFN-60 (p = 0.002) groups. The IFN-30 and IFN-60 groups did not differ. Within IFNbeta-1a-treated patients with primary progressive multiple sclerosis, median UNCR values were significantly higher in clinically stable (no Expanded Disability Status Scale change) compared with progressive patients (p = 0.002). IFNbeta-1a treatment did not significantly influence NOx excretion in patients with primary progressive multiple sclerosis.Conclusions: Urinary neopterin is a potential biomarker to monitor the in vivo effects of IFNbeta-1a in primary progressive multiple sclerosis and other multiple sclerosis sub-types.

9: Thorax, 2010 Jul, 65(7)
Double-stranded RNA induces disproportionate expression of thymic stromal lymphopoietin versus interferon-{beta} in bronchial epithelial cells from donors with asthma.

[Abstract]Background Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that strongly activates dendritic cells and can initiate allergic inflammation. Since exposure to rhinovirus or double-stranded (ds) RNA (a surrogate of viral infection) induces TSLP expression in bronchial epithelial cells (BECs), this cytokine may link innate antiviral responses and the type 2 adaptive immune response. Objective As BECs from donors with asthma have a deficient interferon (IFN) response to rhinovirus infection, a study was undertaken to test the hypothesis that their antiviral response shows a bias towards TSLP production. Methods Primary BECs were grown from subjects with asthma and healthy volunteers. After exposure to dsRNA, interleukin (IL)-8, IFNbeta and TSLP mRNA and protein expression were measured by RT-qPCR and ELISA, respectively. Results dsRNA dose-dependently increased IL-8 expression in BECs with no significant difference between the groups. However, BECs from subjects with asthma expressed less IFNbeta and more TSLP mRNA and protein in response to dsRNA than BECs from those without asthma (median (IQR) 57 (38-82) pg/ml vs 106 (57-214) pg/ml for IFNbeta (p<0.05) and 114 (86-143) pg/ml vs 65 (32-119) pg/ml for TSLP (p<0.05) in response to 10 mug/ml dsRNA for 24 h). Induction of TSLP mRNA by dsRNA was blocked by Toll-like receptor 3 or protein kinase inhibitors or by preventing de novo protein synthesis, but not by neutralisation of type I IFN receptors. Conclusion BECs from subjects with asthma are biased towards higher TSLP and lower IFNbeta production in response to dsRNA, suggesting that viral infection in asthma may lead to an altered mediator profile that biases towards a Th2 immune response.

10: CNS neuroscience & therapeutics, 2010 Jul 7,
The Combination of Interferon-Beta and HMG-CoA Reductase Inhibition in Multiple Sclerosis: Enthusiasm Lost too Soon?

[Abstract]SUMMARY Recent studies support the notion that statins, widely prescribed cholesterol-lowering agents, may target key elements in the immunological cascade leading to inflammation and tissue damage in the pathogenesis of multiple sclerosis (MS). Compelling experimental and observational clinical studies highlighted the possibility that statins may also exert immunomodulatory synergy with approved MS drugs, resulting in several randomized clinical trials testing statins in combination with interferon-beta (IFN-beta). Some data, however, suggest that this particular combination may not be clinically beneficial, and might actually have a negative effect on the disease course in some patients with MS. In this regard, a small North American trial indicated that atorvastatin administered in combination with IFN-beta may increase disease activity in relapsing-remitting MS. Although other trials did not confirm this finding, the enthusiasm for studies with statins dwindled. This review aims to provide a comprehensive overview of the completed clinical trials and reports of the interim analyses evaluating the combination of IFN-beta and statins in MS. Moreover, we try to address the evident question whether usage of this combination routinely requires caution, since the number of IFN-beta-treated MS patients receiving statins for lowering of cholesterol is expected to grow.

11: Multiple sclerosis (Houndmills, Basingstoke, England), 2010 Jul, 16(7)
Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-{beta}1b.

[Abstract]Background: Interferon-beta1b (IFN-beta1b), an effective treatment for multiple sclerosis (MS), lessens disease severity in MS patients. However, the mechanisms of its immunoregulatory and anti-inflammatory effects in MS remain only partially understood. Matrix metalloproteinases (MMP) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) are involved in blood brain barrier disruption and formation of MS lesions. Th1/Th17 cytokines e.g. interleukins IL-12p40, IL-17, and IL-23, are associated with MS disease activity and are significant players in pathogenesis of MS. Objective: During a 1-year prospective study, we serially measured serum MMP-8, MMP-9, TIMP-1, IL-12p40, IL-17, and IL-23 in 24 patients with relapsing-remitting MS. We compared the results to clinical course and to brain magnetic resonance imaging. IFN-beta1b decreased serum MMP-8 and MMP-9 (not TIMP-1). Results: The sustained treatment with IFN-beta1b attenuated the pro-inflammatory environment by significantly reducing the serum IL-12p40, IL-23, and showed a trend for decreasing IL-17. Decreased serum MMP-8, MMP-9, IL-12 and IL-23 levels were correlated with a decrease in the number of contrast-enhanced T2-weighted lesions. Conclusion: Early treatment of MS with IFN-beta1b may stabilize clinical disease by attenuating levels of inflammatory cytokines and MMPs. Serial measurement of inflammatory mediators may serve as sensitive markers to gauge therapeutic responses to IFN-beta1b during the first year of treatment.

12: Journal of neuroimmunology, 2010 Jul 9,
Plasmacytoid dendritic cells in multiple sclerosis: Chemokine and chemokine receptor modulation by interferon-beta.

[Abstract]Plasmacytoid dendritic cells (pDCs) are present in peripheral blood, leptomeninges and demyelinating lesions in patients with multiple sclerosis (MS). The ability of pDCs to produce chemokines and express the chemokine receptor CCR7 in MS is not known. We studied pDCs in MS patients and healthy subjects. The ability of pDCs to up-regulate CCR7 was significantly increased in untreated MS patients as compared to healthy subjects. IFN-beta treatment significantly inhibited TLR9 agonist-specific secretion of chemokines, which are ligands for CCR5-positive Th1 cells (CCL3, CCL4, and CCL5), and impaired TLR9 agonist-induced up-regulation of CCR7 and IFN-alpha in MS patients. This finding represents a new immunomodulatory effect of IFN-beta in patients with multiple sclerosis.

13: Lancet neurology, 2010 Jul, 9(7)
Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis.

[Abstract]The identification of factors that can affect the efficacy of immunomodulatory drugs in relapsing-remitting multiple sclerosis (MS) is important. For the available interferon-beta products, neutralising antibodies (NAb) have been shown to affect treatment efficacy. In June, 2009, a panel of experts in MS and NAbs to interferon-beta therapy convened in Amsterdam, Netherlands, under the auspices of the Neutralizing Antibodies on Interferon beta in Multiple Sclerosis consortium, a European-based project of the 6th Framework Programme of the European Commission, to review and discuss data on NAbs and their practical consequences for the treatment of patients with MS on interferon beta. The panel believed that information about NAbs and other markers of biological activity of interferons (ie, myxovirus resistance protein A [MxA]) can be integrated with clinical and imaging indicators to guide individual treatment decisions. In cases of sustained high-titre NAb positivity and/or lack of MxA bioactivity, a switch to a non-interferon-beta therapy should be considered. In patients who are doing poorly clinically, therapy should be switched irrespective of NAb or MxA bioactivity.

14: Molecular therapy : the journal of the American Society of Gene Therapy, 2010 Jul 6,
Urokinase-Targeted Fusion by Oncolytic Sendai Virus Eradicates Orthotopic Glioblastomas by Pronounced Synergy With Interferon-beta Gene.

[Abstract]Glioblastoma multiforme (GM), the most frequent primary malignant brain tumor, is highly invasive due to the expression of proteases, including urokinase-type plasminogen activator (uPA). Here, we show the potential of our new and powerful recombinant Sendai virus (rSeV) showing uPA-specific cell-to-cell fusion activity [rSeV/dMFct14 (uPA2), named "BioKnife"] for GM treatment, an effect that was synergistically enhanced by arming BioKnife with the interferon-beta (IFN-beta) gene. BioKnife killed human GM cell lines efficiently in a uPA-dependent fashion, and this killing was prevented by PA inhibitor-1. Rat gliosarcoma 9L cells expressing both uPA and its functional receptor uPAR (9L-L/R) exhibited high uPA activity on the cellular surface and were highly susceptible to BioKnife. Although parent 9L cells (9L-P) were resistant to BioKnife and to BioKnife expressing IFN-beta (BioKnife-IFNbeta), cell-cell fusion of 9L-L/R strongly facilitated the expression of IFN-beta, and in turn, IFN-beta significantly accelerated the fusion activity of BioKnife. A similar synergy was seen in a rat orthotopic brain GM model with 9L-L/R in vivo; therefore, these results suggest that BioKnife-IFNbeta may have significant potential to improve the survival of GM patients in a clinical setting.

15: Clinical immunology (Orlando, Fla.), 2010 Jun 25, 51(1)
Natural killer receptors distribution in multiple sclerosis: Relation to clinical course and interferon-beta therapy.

[Abstract]NK cell receptors (NKR) are expressed in subsets of NK and CD8+ T cells, lymphocytes involved in multiple sclerosis (MS) pathogenesis. Clinical implications of NKR expression in MS are unknown. Here, we show that the proportions of CD8+ T cells displaying LILRB1, an inhibitory NKR expressed at late stages of T cell differentiation, were directly related with age and MS duration, and inversely with the immunomodulatory therapy-dependent increase of CD56(bright) NK cells. Similar associations were found for KIR+ and CD56+ CD8+ T cells, whereas no age-related NKR distribution was perceived in controls. Moreover, active MS had lower LILRB1+ NK cells, and IFN-beta-treated patients exhibited a phenotypic profile related to shorter disease evolution. Progressive accumulation of terminally differentiated T lymphocytes and experienced NK cells in MS, presumably stimulated in response to a persistent challenge and modulated by IFN-beta therapy, may support the analysis of NKR distribution as new biomarkers.

16: Journal of neuroimmunology, 2010 Jun 22, 285(26)
Bimodal effect of interferon-beta on astrocyte proliferation and survival: Importance of nuclear factor-kappaB.

[Abstract]Accumulating evidence indicates that interferon-beta (IFN-beta) can modify the complex immunopathogenic scenario causing clinical relapse activity and disease progression in MS. However, the beneficial effects of IFN-beta in MS patients may also depend on non-immune mechanisms, including the modulation of astrocyte function. In the present report, we have shown that, depending on the dose, IFN-beta treatment can either promote astrocyte proliferation and survival, or result astrocyte death. These actions depend, at least in part, on the regulation of nuclear factor-kappa B (NF-kappaB), an inducible transcription factor present in neurons and glia. This bimodal effect of IFN-beta adds a new layer of complexity in the actions of IFN-beta within the CNS.

17: Journal of neuroimmunology, 2010 Jun 21, 285(26)
Pro-inflammatory cytokine and chemokine mRNA blood level in multiple sclerosis is related to treatment response and interferon-beta dose.

[Abstract]Of 37 multiple sclerosis patients, 19 suboptimal responders were randomized to 375 (n=12) or 250microg (n=7) interferon (IFN)-beta-1b. mRNA levels of 23 cytokines, chemokines, and chemokine receptors were quantified by TaqMan((R)) low-density array (TLDA) real-time polymerase chain reaction. Better treatment responses or increased IFN-beta doses were associated with elevated IL-10 and TGF-beta and decreased CXCL10, IL-18, IFN-gamma, and TNF-alpha transcript levels. Adjusting for dose, poor treatment responses resulted in a 4-fold increase in CXCL10 and IFN-gamma expression (Mantel-Haenszel RR=3.74, p<0.0001). CXCL10 and IFN-gamma mRNA levels were reliable indicators of treatment response. TLDA can be used to tailor IFN-beta-1b therapy.

18: Revista de neurologia, 2010 Jul 1, 51(1)
[Livedo reticularis following subcutaneous injection of interferon beta-1b.]

[Abstract]The purpose of this study is to evaluate the primary mechanism through which interferon (IFN)-beta exhibits target-mediated drug disposition (TMDD) and whether the theoretical assumptions of TMDD models are consistent with experimental pharmacokinetic (PK) data. Recombinant murine IFN-beta was administered as an intravenous injection at two dose levels (0.5 and 1 million IU/kg) to male wild-type (WT) and type-I IFN-alpha/beta receptor subunit (IFNAR-1) knockout (KO) mice (A129S7/SvEvBrd strain). Sampling was conducted at various times (n = 3/time point), and plasma was analyzed for IFN-beta concentrations using a validated enzyme-linked immunosorbent assay. The pharmacodynamic (PD) biomarker was IP-10 mRNA that was isolated from the distal femur bone and quantified using reverse transcription-polymerase chain reaction. An integrated model that includes rapid-binding TMDD and an indirect mechanism of drug action was used to characterize the PK/PD profiles. For an experimental control, PK profiles of recombinant murine erythropoietin (muEPO), another drug that exhibits TMDD, were determined after a single intravenous dose (0.5 microg/kg) in WT and KO animals. The concentration-time profiles for IFN-beta differed substantially at initial times for the WT and KO mice at the same dose levels. These differences are characteristic of ligands exhibiting receptor-mediated disposition and were well described by a rapid-binding TMDD model. No differences in muEPO PK were observed in the control study. In summary, the intact IFNAR receptor is a primary regulator of in vivo IFN-beta exposure. An integrated PK/PD model was successfully used to assess the receptor-mediated disposition and dynamics of IFN-beta.

19: Hepatology research : the official journal of the Japan Society of Hepatology, 2010 Jun 8, 5(6)
Two week induction of interferon-beta followed by pegylated interferon alpha-2b and ribavirin for chronic infection with hepatitis C.

[Abstract]Objectives: To elucidate the efficacy of interferon (IFN)-beta induction therapy followed by pegylated IFN alpha and ribavirin for chronic infection with hepatitis C virus (HCV). Methods: Patients chronically infected with HCV genotype 1, high titer were enrolled. Twice daily bolus injections of 3 million units IFN-beta were administered for 14 days. Thereafter, weekly injection of pegylated IFN alpha 2b and daily intake of ribavirin were followed. Therapy duration was adjusted according to the response to the therapy. When time to an undetectable HCV-RNA was 1, 2, 4, 8, and 12 weeks, total duration of therapy was 12, 24, 36, 48 and 60 weeks, respectively. Patients who failed to achieve an undetectable HCV-RNA within 12 weeks discontinued therapy on 12 week. Results: Among the 101 patients treated, 56 (55.4%) achieved sustained virological response (SVR). SVR rate for each treatment duration was 10/10 for 12 weeks, 12/14 for 24 weeks, 18/19 for 36 weeks, 15/26 for 48 weeks, 1/4 for 60 weeks and 0/28 for patients who discontinued therapy at 12 weeks. Mean time to an undetectable HCV-RNA was 35.5 +/- 2.7 days. Mean therapy duration was 27.3 +/- 1.4 weeks. Using a cut off value of 21.5 fmol/L of HCV core-antigen in the first week, SVR could be predicted by sensitivity of 0.91 and specificity of 0.78. Conclusion: IFN-beta induction therapy resulted in acceptable SVR rates despite short therapy duration. Steep reduction of HCV by IFN-beta enables us to predict SVR in the first week of therapy.

20: PloS one, 2010, 5(6)
Acetaminophen Modulates the Transcriptional Response to Recombinant Interferon-beta.

[Abstract]BACKGROUND: Recombinant interferon treatment can result in several common side effects including fever and injection-site pain. Patients are often advised to use acetaminophen or other over-the-counter pain medications as needed. Little is known regarding the transcriptional changes induced by such co-administration. METHODOLOGY/PRINCIPAL FINDINGS: We tested whether the administration of acetaminophen causes a change in the response normally induced by interferon-beta treatment. CD-1 mice were administered acetaminophen (APAP), interferon-beta (IFN-beta) or a combination of IFN-beta+APAP and liver and serum samples were collected for analysis. Differential gene expression was determined using an Agilent 22 k whole mouse genome microarray. Data were analyzed by several methods including Gene Ontology term clustering and Gene Set Enrichment Analysis. We observed a significant change in the transcription profile of hepatic cells when APAP was co-administered with IFN-beta. These transcriptional changes included a marked up-regulation of genes involved in signal transduction and cell differentiation and down-regulation of genes involved in cellular metabolism, trafficking and the IkappaBK/NF-kappaB cascade. Additionally, we observed a large decrease in the expression of several IFN-induced genes including Ifit-3, Isg-15, Oasl1, Zbp1 and predicted gene EG634650 at both early and late time points. CONCLUSIONS/SIGNIFICANCE: A significant change in the transcriptional response was observed following co-administration of IFN-beta+APAP relative to IFN-beta treatment alone. These results suggest that administration of acetaminophen has the potential to modify the efficacy of IFN-beta treatment.

21: Lancet neurology, 2010 Jun 7, 74(23)
Methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN study): a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial.

[Abstract]BACKGROUND: Interferon beta is commonly used to treat patients with relapsing-remitting multiple sclerosis; however, the treatment is only partially effective in reducing relapses and progression of disability. Corticosteroids are used to treat relapses in patients with multiple sclerosis. We therefore aimed to investigate the combination of cyclic methylprednisolone and interferon beta for the treatment of relapsing-remitting multiple sclerosis. METHODS: In 2001, we designed a multicentre, double-blind, randomised, parallel-group trial, termed the methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN) study. Patients were recruited between October, 2002, and March, 2005 from 50 neurology departments in eight countries. We included treatment-naive patients with relapsing-remitting multiple sclerosis who had an expanded disability status scale (EDSS) score of 4 or less. Patients all started to receive interferon beta-1a and after 3 months were randomly assigned to add-on methylprednisolone or placebo 500 mg/day orally for 3 consecutive days per month for 3-4 years. Placebo tablets were identical to methylprednisolone tablets. Treating physicians, examining physicians, and patients were masked to treatment allocation. Patients were clinically assessed every 3 months and had brain MRI at baseline and 3 years later. The primary outcome was time to onset of disability progression, according to an increase in EDSS score sustained over 6 months. All patients who received at least one dose of study drug were included in all planned analyses. This trial is registered with ClinicalTrials.gov, NCT00168766. FINDINGS: 341 patients were randomly assigned to methylprednisolone (n=172) or placebo (n=169); 171 patients in the methylprednisolone group and 167 in the placebo group received at least one dose of study drug. 90 patients had sustained disability progression: 44 of 167 in the methylprednisolone group and 46 of 171 in the placebo group. The time to sustained progression did not differ between groups (hazard ratio 0.879, 95% CI 0.566-1.365; p=0.57). There were 1436 adverse events, 24 of which were serious, in the methylprednisolone group and 1070 events, 35 of which were serious, in the placebo group. INTERPRETATION: Monthly pulses of methylprednisolone in combination with interferon beta-1a do not seem to affect disability progression any more than interferon beta-1a treatment alone. More research is required to assess whether this treatment regimen might benefit particular subsets of patients. FUNDING: Biogen Idec.

22: Multiple sclerosis (Houndmills, Basingstoke, England), 2010 Jun 9, 201(12)
Multiple sclerosis patients lacking oligoclonal bands in the cerebrospinal fluid are less likely to develop neutralizing antibodies against interferon beta.

[Abstract]Multiple sclerosis patients without cerebrospinal fluid oligoclonal IgG bands have been proposed to constitute an immunogenetically distinct subgroup of multiple sclerosis that may also differ in terms of prognosis. A proportion of patients with multiple sclerosis receiving IFNbeta develop neutralizing antibodies, which interfere with treatment efficacy. Evidence suggests that the likelihood of developing neutralizing antibodies is partly genetically determined. Here, we hypothesized that absence of oligoclonal IgG bands reflects a property of B-cell responses in oligoclonal IgG band-negative patients characterized by a lessened propensity to develop neutralizing antibodies. We aimed to compare the development of neutralizing antibodies against IFNbeta between oligoclonal IgG band-negative and oligoclonal IgG band-positive multiple sclerosis patients. Treatment, oligoclonal IgG band and neutralizing antibody information was obtained for 2219 patients from the Swedish multiple sclerosis registry and the Swedish neutralizing antibody registry. Additional data on genotype was available for 532 patients. A correlation was found between oligoclonal IgG band negativity and neutralizing antibody negativity (p = 0.02). This difference was confined to neutralizing antibodies against IFNbeta-1a, since oligoclonal IgG band-negative patients were, to a lesser extent, neutralizing antibody positive compared with oligoclonal IgG band-positive patients if treated with IFNbeta-1a (12% vs. 23%; p = 0.005). No difference was observed for IFNbeta-1b-treated patients (44% vs. 46%). We propose that oligoclonal IgG band-negative patients differ immunologically from oligoclonal IgG band-positive patients, potentially influenced by distinct HLA-DRB1 alleles.

23: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2010 Jun 8, 201(12)
n-Dodecyl-beta-D: -Maltoside Inhibits Aggregation of Human Interferon-beta-1b and Reduces Its Immunogenicity.

[Abstract]The development of neutralizing antibodies to the protein drug interferon-beta is a significant impediment to its use in the treatment of multiple sclerosis. Neutralizing antibodies to interferon-beta arise from aggregation of the peptide during manufacturing and storage. We tested the ability of dodecylmaltoside, a nontoxic alkylsaccharide surfactant, to reduce aggregation of interferon-beta in vitro and to reduce its immunogenicity in vivo. Interferon-beta, in solution with and without dodecylmaltoside, was periodically evaluated for aggregation by light scatter for 1 month. Interferon-beta, with and without dodecylmaltoside, was given 3 days/week for 1 month to mice; the sera of these mice were analyzed for anti-interferon-beta antibodies by ELISA. Dodecylmaltoside reduces the aggregation of interferon-beta in vitro and its immunogenicity in vivo. Our positive findings warrant additional tests of dodecylmaltoside as a therapeutic adjuvant in rodent models of multiple sclerosis.

24: Neurology, 2010 Jun 8, 74(23)
Cross-sectional study assessing long-term safety of interferon-beta-1b for relapsing-remitting MS.

[Abstract]OBJECTIVE: The 16-Year Long-Term Follow-Up (LTF) to the pivotal interferon-beta-1b (IFNbeta-1b) trial explored clinical, MRI, cognitive, and patient-reported outcomes. Here, we report the safety assessments. METHODS: In the pivotal study, 372 patients were randomized to placebo (n = 123), IFNbeta-1b 50 microg (n = 125), or IFNbeta-1b 250 microg (n = 124) subcutaneously every other day for up to 5 years. Sixteen years later, patients were asked to participate in this cross-sectional follow-up study. No particular therapy was stipulated during follow-up. Adverse events experienced since the pivotal trial were recorded. Neutralizing antibodies (NAbs) to IFNbeta-1b were measured using the myxovirus protein A induction assay. Statistical analyses were descriptive. RESULTS: In total, 88.2% of patients (328/372) were identified. Some centers achieved 100% ascertainment, obviating selection bias. Treatment-related adverse events (e.g., leukopenia and liver and thyroid dysfunction) reported by LTF participants were in keeping with those previously established. Based on a follow-up period that includes 2,000 patient-years of IFNbeta-1b treatment, no new adverse events were observed that were associated with long-term IFNbeta-1b exposure. By LTF, NAbs to IFNbeta-1b disappeared in the majority (76%) of NAb-positive patients. NAb status during the pivotal study appeared to have no impact on long-term clinical and MRI outcomes. There were more deaths among patients assigned to placebo in the pivotal study (20/109 [18.3%]) compared with patients who received IFNbeta-1b 50 microg (9/108 [8.3%]) or IFNbeta-1b 250 microg (6/111 [5.4%]). CONCLUSION: The results from the 16-Year Long-Term Follow-Up study support the long-term safety of interferon-beta-1b therapy in multiple sclerosis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that patients with relapsing-remitting MS taking IFNbeta-1b 50 microg or 250 microg subcutaneously every other day for up to 5 years, with subsequent unspecified treatment, have fewer deaths after 16 years of follow-up than similar patients on placebo for up to 5 years, with subsequent unspecified treatment (risk difference 11.5%, 95% confidence interval 4-19).

25: Immunology, 2010 May 26, 31(3)
Enhancement of anti-Aspergillus T helper type 1 response by interferon-beta-conditioned dendritic cells.

[Abstract]Summary Although data show the importance of type I interferons (IFNs) in the regulation of the innate and adaptive immunity elicited in response to viral, bacterial and parasitic infections, the functional activities of these cytokines during fungal infections are poorly understood. We examined here the impact of IFN-beta on the response of human monocyte-derived dendritic cells (DCs) infected in vitro with Aspergillus fumigatus. Having found that A. fumigatus-infected DCs do not express IFN-beta, we evaluated the effect of the exogenous addition of IFN-beta on the maturation of human DCs induced by the infection with A. fumigatus conidia. Although the phagocytosis of the fungus was not affected by IFN-beta treatment, the expression of CD86 and CD83 induced upon A. fumigatus challenge was enhanced in IFN-beta-conditioned DCs, which also showed an increased expression of IL-27 and IL-12p70, members of IL-12 family. Through these modifications, IFN-beta improved the capacity of DCs to promote an anti-Aspergillus T helper type 1 response, as evaluated by mixed leucocyte reaction, which plays a crucial role in the control of invasive aspergillosis. Our results identified a novel effect of IFN-beta on anti-Aspergillus immune responses which, in turn, might open new perspectives on the use of IFN-beta in immunotherapy for fungal infections aimed at enhancing the immunological functions of DCs.

26: Pharmaceutical research, 2010 May 25, 31(3)
Aggregated Recombinant Human Interferon Beta Induces Antibodies but No Memory in Immune-Tolerant Transgenic Mice.

[Abstract]PURPOSE: To study the influence of protein aggregation on the immunogenicity of recombinant human interferon beta (rhIFNbeta) in wild-type mice and transgenic, immune-tolerant mice, and to evaluate the induction of immunological memory. METHODS: RhIFNbeta-1b and three rhIFNbeta-1a preparations with different aggregate levels were injected intraperitoneally in mice 15x during 3 weeks, and the mice were rechallenged with rhIFNbeta-1a. The formation of binding (BABs) and neutralizing antibodies (NABs) was monitored. RESULTS: Bulk rhIFNbeta-1a contained large, mainly non-covalent aggregates and stressed rhIFNbeta-1a mainly covalent, homogeneous (ca. 100 nm) aggregates. Reformulated rhIFNbeta-1a was essentially aggregate-free. All products induced BABs and NABs in wild-type mice. Immunogenicity in the transgenic mice was product dependent. RhIFNbeta-1b showed the highest and reformulated rhIFNbeta-1a the lowest immunogenicity. In contrast with wild-type mice, transgenic mice did not show NABs, nor did they respond to the rechallenge. CONCLUSIONS: The immunogenicity of the products in transgenic mice, unlike in wild-type mice, varied. In the transgenic mice, neither NABs nor immunological memory developed. The immunogenicity of rhIFNbeta in a model reflecting the human immune system depends on the presence and the characteristics of aggregates.

27: Multiple sclerosis (Houndmills, Basingstoke, England), 2010 May 20, 31(3)
Simvastatin treatment in patients with relapsing-remitting multiple sclerosis receiving interferon beta 1a: a doubleblind randomized controlled trial.

[Abstract]Objectives: This study was conducted to evaluate the effect of simvastatin (40 mg/day) as an adjuvant therapy to interferon beta (IFNb 1a, 30 mug once weekly) in relapsing-remitting multiple sclerosis patients, compared with placebo. Methods: We enrolled 85 patients with relapsing-remitting multiple sclerosis (71% female) who were already receiving IFNb 1a (Avonex), with Expanded Disability Status Scale score of less than 5.0. The patients were assigned (in random and double-blinded fashion) into the two groups of simvastatin and placebo. All patients continued to receive their current IFNb treatment. The outcome measures were total relapse rate, Expanded Disability Status Scale score, and the number of gadolinium-enhanced (Gd+) and new T2 lesions in magnetic resonance imaging after a 1-year follow-up. We used Mann-Whitney and one-way multivariate analysis of variances to analyze the data. Results: Four patients in the placebo and two in the simvastatin group prematurely withdrew from the study due to experiencing two attacks. The total attack number in the simvastatin group was significantly lower than placebo group (moderate effect size r = 0.29) (p = 0.01). The final Expanded Disability Status Scale scores were lower in the simvastatin group (1.01 +/- 1.40, mean +/- SD) than in the placebo group (1.73 +/- 1.49, mean +/- SD), but this difference was not significant after controlling the baseline Expanded Disability Status Scale score (p = 0.07). In the simvastatin group, the mean +/- SD of gadolinium-enhanced and new T2 lesions were 0.66 +/- 1.18 and 3.39 +/- 3.55, respectively, (compared with 0.74 +/- 1.21 and 3.39 +/- 3.55 in the placebo group). Although there was a decreasing trend in lesions on magnetic resonance imaging, this difference was not statistically significant (p = 0.62). The combination therapy was safe and well tolerated, and no serious adverse effect was noted. Conclusion: Our study supports the safety and efficacy of simvastatin as an add-on therapy to INFb 1a in patients with relapsing-remitting multiple sclerosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00668343.This interventional study provides Class I evidence stating that adding simvastatin 40 mg/day to IFNb 1a 30 mug a week in patients with relapsing-remitting multiple sclerosis may reduce the relapse rate (moderate effect size r = 0.29) (p = 0.01) compared with treatment with IFNb 1a alone.

28: PloS one, 2010, 5(5)
Novel approaches to detect serum biomarkers for clinical response to interferon-beta treatment in multiple sclerosis.

[Abstract]Interferon beta (IFNbeta) is the most common immunomodulatory treatment for relapsing-remitting multiple sclerosis (RRMS). However, some patients fail to respond to treatment. In this study, we identified putative clinical response markers in the serum and plasma of people with multiple sclerosis (MS) treated with IFNbeta. In a discovery-driven approach, we use 2D-difference gel electrophoresis (DIGE) to identify putative clinical response markers and apply power calculations to identify the sample size required to further validate those markers. In the process we have optimized a DIGE protocol for plasma to obtain cost effective and high resolution gels for effective spot comparison. APOA1, A2M, and FIBB were identified as putative clinical response markers. Power calculations showed that the current DIGE experiment requires a minimum of 10 samples from each group to be confident of 1.5 fold difference at the p<0.05 significance level. In a complementary targeted approach, Cytometric Beadarray (CBA) analysis showed no significant difference in the serum concentration of IL-6, IL-8, MIG, Eotaxin, IP-10, MCP-1, and MIP-1alpha, between clinical responders and non-responders, despite the association of these proteins with IFNbeta treatment in MS.

29: The Journal of infectious diseases, 2010 May 12, 292(1-2)
Significance of the Myxovirus Resistance A (MxA) Gene -123C>A Single-Nucleotide Polymorphism in Suppressed Interferon beta Induction of Severe Acute Respiratory Syndrome Coronavirus Infection.

[Abstract]Myxovirus resistance A (MxA) is an antiviral protein induced by interferon alpha and beta (IFN-alpha, IFN-beta) that can inhibit viral replication. The minor alleles of the -88G>T and -123C>A MxA promoter single-nucleotide polymorphisms (SNPs) are associated with increased promoter activity and altered response to IFN-alpha and IFN-beta treatment. Here, we demonstrate that the -123A minor allele provided stronger binding affinity to nuclear proteins extracted from IFN-beta-untreated cells than did the wild-type allele, whereas the -88T allele showed preferential binding after IFN-beta stimulation. Endogenous IFN-alpha and IFN-beta induction can be suppressed in severe acute respiratory syndrome (SARS) coronavirus infection. In support of our in vitro findings, a large case-control genetic-association study for SARS coronavirus infection confirmed that the -123A minor-allele carriers were significantly associated with lower risk of SARS coronavirus infection, whereas the -88T minor-allele carriers were insignificant after adjustment for confounding effects. This suggests that -123C>A plays a more important role in modulating basal MxA expression, thus contributing more significantly to innate immune response against viral infections that suppress endogenous IFN-alpha and IFN-beta induction such as SARS coronavirus.

30: Revista de neurologia, 2010 May 1, 50(9)
[Long term effect of interferon-beta on disease severity in relapsing-remitting multiple sclerosis patients]

[Abstract]AIM: To investigate the long-term impact of interferon-beta (IFNbeta) therapy on disease severity in relapsing-remitting multiple sclerosis (RRMS) patients. PATIENTS AND METHODS: We included 210 patients with RRMS and indication for immunomodulatory treatment followed up at least for nine years. We compared between treated and untreated groups: time since the beginning of the disease to reach EDSS 6.0 and time to conversion to secondary progressive multiple sclerosis. Log-rank test was used to compare outcomes between groups, p < 0.05 were considered significant. RESULTS: 160 patients were IFNbeta-treated, 50 untreated. The percentage of patients that converted to SPMS after 9 years of follow-up was 7.1% for treated vs. 21.7% for untreated (p = 0.022; RR = 0.32; 95% CI = 0.13-0.74). About 7.7% for IFNbeta-treated vs. 18.7% of untreated patients reached EDSS 6.0 after the period of follow-up (p = 0.032; RR = 0.4; 95% CI = 0.16-0.95). Mean time to reach EDSS 6.0 was 8.1 years for IFNbeta-treated vs. 5.8 years for untreated patients (p < 0.001). CONCLUSION: Long term treatment with IFNbeta slows progression in MS measured by EDSS and time to conversion to secondary progressive multiple sclerosis.

31: International journal of molecular medicine, 2010 Jun, 25(6)
Effect of ribavirin and interferon beta on miRNA profile in the hepatitis C virus subgenomic replicon-bearing Huh7 cells.

[Abstract]Hepatitis C virus (HCV) infection is still a major global health issue despite decades of research. The liver-specific microRNA-122 (miR-122) can stimulate HCV replication/translation in vitro, indicating that miR-122 contributes to pathogenesis of HCV. However, it remains controversial whether interferon (IFN) inhibits HCV via modulating miR-122 expression. The underlying mechanism of ribavirin (RBV) in enhancing IFN treatment for HCV patients has yet to be explored. We investigated the relationship between miR-122 expression and anti-HCV activity of IFN beta in combination with RBV in vitro, due to difficulty accessing an HCV animal model. Upregulation of ISG54 mRNA or cytostatic effect was detected in Huh7 and HCV replicon cell lines in response to IFN beta or RBV stimulation, respectively. It was found that IFN beta and/or RBV suppressed miR-122 expression marginally, with a synergetic anti-HCV effect between IFN beta and RBV. Marginal modification of other miRNAs was also observed in these cell lines, using miRNA array following IFN beta and RBV treatment. Taken together, our data suggest that miRNAs are not crucial in anti-HCV action, following IFN beta and/or RBV stimulation in vitro.

32: The Journal of pharmacology and experimental therapeutics, 2010 Apr 20, 58(8)
Type I Interferon Receptor is a Primary Regulator of Target-mediated Drug Disposition of Interferon-{beta} in Mice.

[Abstract]The purpose of this study is to evaluate the primary mechanism through which interferon (IFN)-beta exhibits target-mediated drug disposition (TMDD) and whether the theoretical assumptions of TMDD models are consistent with experimental pharmacokinetic (PK) data. Recombinant murine IFN-beta was administered as an intravenous injection at two dose levels (0.5 and 1 million IU/kg) to male wild-type (WT) and type-I IFN alpha/beta receptor subunit (IFNAR-1) knockout (KO) mice (A129S7/SvEvBrd strain). Sampling was conducted at various time points (n=3/time point), and plasma was analyzed for IFN-beta concentrations using a validated ELISA. The pharmacodynamic (PD) biomarker was IP-10 mRNA that was isolated from the distal femur bone and quantified using RT-PCR. An integrated model that includes rapid-binding TMDD and an indirect mechanism of drug action was used to characterize the PK/PD profiles. For an experimental control, PK profiles of recombinant murine erythropoietin (muEPO), another drug that exhibits TMDD, were determined following a single intravenous dose (0.5mug/kg) in WT and KO animals. The concentration-time profiles for IFN-beta differed substantially at initial times for the WT and KOmice at the same dose levels. These differences are characteristic of ligands exhibiting receptor-mediated disposition and were well described by a rapidbinding TMDD model. No differences in muEPO PK were observed in the control study. In summary, the intact IFNAR receptor is a primary regulator of in vivo IFN-beta exposure. An integrated PK/PD model was successfully used to assess the receptor-mediated disposition and dynamics of IFN-beta.

33: The Journal of biological chemistry, 2010 Jun 25, 285(26)
Negative Role of RIG-I Serine 8 Phosphorylation in the Regulation of Interferon-{beta} Production.

[Abstract]RIG-I (retinoic acid-inducible gene I) and TRIM25 (tripartite motif protein 25) have emerged as key regulatory factors to induce interferon (IFN)-mediated innate immune responses to limit viral replication. Upon recognition of viral RNA, TRIM25 E3 ligase binds the first caspase recruitment domain (CARD) of RIG-I and subsequently induces lysine 172 ubiquitination of the second CARD of RIG-I, which is essential for the interaction with downstream MAVS/IPS-1/CARDIF/VISA and, thereby, IFN-beta mRNA production. Although ubiquitination has emerged as a major factor involved in RIG-I activation, the potential contribution of other post-translational modifications, such as phosphorylation, to the regulation of RIG-I activity has not been addressed. Here, we report the identification of serine 8 phosphorylation at the first CARD of RIG-I as a negative regulatory mechanism of RIG-I-mediated IFN-beta production. Immunoblot analysis with a phosphospecific antibody showed that RIG-I serine 8 phosphorylation steady-state levels were decreased upon stimulation of cells with IFN-beta or virus infection. Substitution of serine 8 in the CARD RIG-I functional domain with phosphomimetic aspartate or glutamate results in decreased TRIM25 binding, RIG-I ubiquitination, MAVS binding, and downstream signaling. Finally, sequence comparison reveals that only primate species carry serine 8, whereas other animal species carry an asparagine, indicating that serine 8 phosphorylation may represent a primate-specific regulation of RIG-I activation. Collectively, these data suggest that the phosphorylation of RIG-I serine 8 operates as a negative switch of RIG-I activation by suppressing TRIM25 interaction, further underscoring the importance of RIG-I and TRIM25 connection in type I IFN signal transduction.

34: Virology, 2010 Apr 7, 292(1-2)
Epstein-Barr virus BRLF1 inhibits transcription of IRF3 and IRF7 and suppresses induction of interferon-beta.

[Abstract]Activation of interferon regulatory factors (IRFs) 3 and 7 is essential for the induction of Type I interferons (IFN) and innate antiviral responses, and herpesviruses have evolved mechanisms to evade such responses. We previously reported that Epstein-Barr virus BZLF1, an immediate-early (IE) protein, inhibits the function of IRF7, but the role of BRLF1, the other IE transactivator, in IRF regulation has not been examined. We now show that BRLF1 expression decreased induction of IFN-beta, and reduced expression of IRF3 and IRF7; effects were dependent on N- and C-terminal regions of BRLF1 and its nuclear localization signal. Endogenous IRF3 and IRF7 RNA and protein levels were also decreased during cytolytic EBV infection. Finally, production of IFN-beta was decreased during lytic EBV infection and was associated with increased susceptibility to superinfection with Sendai virus. These data suggest a new role for BRLF1 with the ability to evade host innate immune responses.

35: Cancer gene therapy, 2010 Apr 9, 292(1-2)
Oncolytic measles viruses encoding interferon beta and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy.

[Abstract]Mesothelioma usually leads to death within 8-14 months of diagnosis. To increase the potency of oncolytic measles viruses (MVs) for mesothelioma therapy, we inserted the interferon beta (IFNbeta) gene alone or with the human thyroidal sodium iodide symporter (NIS) gene into attenuated MV of the Edmonston lineage. The corresponding mouse IFNbeta (mIFNbeta) viruses, MV-mIFNbeta and MV-mIFNbeta-NIS, successfully propagated in human mesothelioma cells, leading to intercellular fusion and cell death. High levels of mIFNbeta were detected in the supernatants of the infected cells, and radioiodine uptake was substantial in the cells infected with MV-mIFNbeta-NIS. MV with mIFNbeta expression triggered CD68-positive immune cell infiltration 2-4 times higher than MV-GFP injected into the tumor site. The numbers of CD31-positive vascular endothelial cells within the tumor were decreased at day 7 after intratumoral injection of MV-mIFNbeta or MV-mIFNbeta-NIS, but not after MV-GFP and PBS administration. Immunohistochemical analysis showed that MV-mIFNbeta changed the microenvironment of the mesothelioma by increasing innate immune cell infiltration and inhibiting tumor angiogenesis. Oncolytic MVs coding for IFNbeta effectively retarded growth of human mesotheliomas and prolonged survival time in several mesothelioma tumor models. The results suggest that oncolytic MVs that code for IFNbeta and NIS will be potent and versatile agents for the treatment of human mesothelioma.Cancer Gene Therapy advance online publication, 9 April 2010; doi:10.1038/cgt.2010.10.

36: The Journal of general virology, 2010 Apr 7, 292(1-2)
The Hepatitis B Virus Polymerase Inhibits Rig-I- And Toll-Like Receptor 3-Mediated Interferon-{beta} Induction In Human Hepatocytes Through Interference With Interferon Regulatory Factor 3 Activation And Dampening Of The Interaction Between Tbk1/Ikk{varep

[Abstract]Hepatitis B virus (HBV) infection is still one of the most serious health problems worldwide. While studies have shown that HBV impairs interferon (IFN) production from dendritic cells (DCs) in chronic hepatitis B patients, it remains unknown whether HBV inhibits interferon production in human hepatocytes. Using transient transfection assays in primary human hepatocyte PH5CH8 cell line, we demonstrate that HBV polymerase inhibits IFN-beta promoter activity induced by Newcastle Disease Virus (NDV), Sendai Virus (SeV) or poly(I:C) in a dose-dependent manner, while ectopic expression of HBV Core and X proteins has no effect on IFN-beta promoter activity. In addition, HBV polymerase blocks cellular IFN-beta expression and consequent antiviral immunity revealed by an infection protection assay. Furthermore, over-expression of key molecules on the IFN-beta induction axis, together with HBV polymerase, resulted in a block of IFN-beta promoter activity triggered by RIG-I, IPS-1, TRIF, TBK1 and IKKepsilon, but not by an IFN regulatory factor 3 dominant-positive mutant (IRF3-5D); suggesting that HBV polymerase prevents IFN-beta expression at the TBK1/IKKepsilon level. Further studies show that HBV polymerase inhibits phosphorylation, dimerization and nuclear translocation of IRF3, in response to SeV infection. Finally, we demonstrate that HBV polymerase-mediated dampening of the interaction between TBK1/IKKepsilon and DDX3 can be involved in the inhibitory effect on IFN-beta induction. Taken together, our findings reveal a novel role of HBV polymerase in HBV counteraction of IFN-beta production in human hepatocytes.

37: Journal of agricultural and food chemistry, 2010 Mar 31, 18(4)
Isoliquiritigenin Suppresses the Toll-Interleukin-1 Receptor Domain-Containing Adapter Inducing Interferon-beta (TRIF)-Dependent Signaling Pathway of Toll-Like Receptors by Targeting TBK1.

[Abstract]Toll-like receptors (TLRs) play an important role in induction of innate immune responses. TLRs can trigger the activation of myeloid differential factor 88 (MyD88)- and Toll-interleukin-1 receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent downstream signaling pathways. Expression of more than 70% of lipopolysaccharide (LPS)-induced target genes is mediated through a TRIF-dependent signaling pathway. To evaluate the therapeutic potential of isoliquiritigenin (ILG), we examined its effect on signal transduction via the TRIF-dependent pathway of TLRs. ILG inhibited interferon regulatory factor 3 activation induced by LPS or polyinosinic-polycytidylic acid, as well as interferon-inducible genes, such as interferon-inducible protein-10. ILG attenuated ligand-independent activation of IRF3 induced by TRIF or TBK1. Furthermore, ILG inhibited TBK1 kinase activity in vitro. Together, these results demonstrate that TBK1 is the molecular target of ILG, resulting in the downregulation of the TRIF-dependent signaling pathways of TLRs.

38: Journal of cardiac failure, 2010 Apr, 16(4)
Interferon beta-1b Therapy in Chronic Viral Dilated Cardiomyopathy-Is There a Role for Specific Therapy?

[Abstract]BACKGROUND: Myocardial biopsy can be used for the detection of viral genome in dilated cardiomyopathy (DCM). Pilot studies have previously reported beneficial effects on clinical outcome and safety of an antiviral therapy using interferon beta-1b in chronic viral DCM. METHODS AND RESULTS: Myocardial biopsies were taken from patients with DCM. Using polymerase chain reaction and Southern Blot analysis, viral genome could be detected in 49% of patients. In 42 patients with viral infection, off-label use with interferon beta-1b was initiated. A further 68 patients formed the control group. The outcome was evaluated after follow-up with echocardiography, exercise electrocardiogram, and New York Heart Association class. A total of 81 men and 29 women with a median left ventricular ejection fraction of 34% were included. The follow-up period was 36 months. In 33 (79%) patients with interferon beta-1b treatment, minor adverse reactions occurred, but no major adverse events were reported. No significant benefit for interferon beta-1b treatment on clinical outcome could be detected during follow-up. CONCLUSIONS: Off-label use with interferon beta-1b in patients with viral DCM is feasible and safe under routine clinical practice. Concerning the herein evaluated clinical outcome parameters, promising results from pilot studies could not be confirmed. High prevalence of parvovirus B19 (92%) might influence the results.

39: Nature medicine, 2010 Mar 28, 9(4)
T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis.

[Abstract]Interferon-beta (IFN-beta) is the major treatment for multiple sclerosis. However, this treatment is not always effective. Here we have found congruence in outcome between responses to IFN-beta in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting multiple sclerosis (RRMS). IFN-beta was effective in reducing EAE symptoms induced by T helper type 1 (T(H)1) cells but exacerbated disease induced by T(H)17 cells. Effective treatment in T(H)1-induced EAE correlated with increased interleukin-10 (IL-10) production by splenocytes. In T(H)17-induced disease, the amount of IL-10 was unaltered by treatment, although, unexpectedly, IFN-beta treatment still reduced IL-17 production without benefit. Both inhibition of IL-17 and induction of IL-10 depended on IFN-gamma. In the absence of IFN-gamma signaling, IFN-beta therapy was ineffective in EAE. In RRMS patients, IFN-beta nonresponders had higher IL-17F concentrations in serum compared to responders. Nonresponders had worse disease with more steroid usage and more relapses than did responders. Hence, IFN-beta is proinflammatory in T(H)17-induced EAE. Moreover, a high IL-17F concentration in the serum of people with RRMS is associated with nonresponsiveness to therapy with IFN-beta.

40: Journal of the neurological sciences, 2010 Mar 15, 201(6)
Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis.

[Abstract]The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNbeta-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300mg (n=589) or placebo (n=582) intravenously every 4weeks plus IFNbeta-1a 30microg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2years, 67% of patients receiving natalizumab plus IFNbeta-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNbeta-1a alone. The mean change from baseline in T2 lesion volume over 2years decreased in patients receiving natalizumab plus IFNbeta-1a and increased in those receiving IFNbeta-1a alone (-277.5mm(3) versus 525.6mm(3); p<0.001). Compared with IFNbeta-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2years (1821.3mm(3) versus 2210.5mm(3); p<0.001), a smaller mean number of new T1-hypointense lesions over 2years (2.3 versus 4.1; p<0.001), and a slower rate of brain atrophy during the second year of therapy (-0.31% versus -0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNbeta-1a alone.

41: Expert opinion on pharmacotherapy, 2010 Mar 15, 10(4)
Good results for early treatment of clinically isolated syndrome prior to multiple sclerosis with interferon beta-1b and glatiramer group.

[Abstract]The first sign of developing multiple sclerosis is a clinically isolated syndrome that resembles a multiple sclerosis relapse. Objective/methods: The objective was to review the clinical trials of two medicines in clinically isolated syndromes (interferon beta and glatiramer acetate) to determine whether they prevent progression to definite multiple sclerosis. In the BENEFIT trial, after 2 years, 45% of subjects in the placebo group developed clinically definite multiple sclerosis; the rate was lower in the interferon beta-1b group. All subjects were then offered interferon beta-1b, and the original interferon beta-1b group became the early-treatment group and the placebo group became the delayed-treatment group. After 5 years, the number of subjects with clinical definite multiple sclerosis remained lower in the early-treatment than in the late-treatment group. In the PreCISe trial, after 2 years, the time for 25% of the subjects to convert to definite multiple sclerosis was prolonged in the glatiramer group. Interferon beta-1b and glatiramer acetate slow the progression of clinically isolated syndromes to definite multiple sclerosis. However, it is not known whether this early treatment slows the progression to the physical disabilities experienced in multiple sclerosis.

42: Cytotherapy, 2010 Mar 15, 10(4)
Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment.

[Abstract]Abstract Background aims. Because of the inflammatory nature and extensive stromal compartment in pancreatic tumors, we investigated the role of mesenchymal stromal cells (MSC) to engraft selectively in pancreatic carcinomas and serve as anti-tumor drug delivery vehicles to control pancreatic cancer progression. Methods. Human pancreatic carcinoma cells, PANC-1, expressing renilla luciferase were orthotopically implanted into SCID mice and allowed to develop for 10 days. Firefly luciferase-transduced MSC or MSC expressing interferon (IFN)-beta were then injected intraperitoneally weekly for 3 weeks. Mice were monitored by bioluminescent imaging for expression of renilla (PANC-1) and firefly (MSC) luciferase. Results. MSC selectively homed to sites of primary and metastatic pancreatic tumors and inhibited tumor growth (P=0.032). The production of IFN-beta within the tumor site by MSC-IFN-beta further suppressed tumor growth (P=0.0000083). Prior studies indicated that MSC home to sites of inflammation; therefore, we sought to alter the tumor microenvironment through treatment with a potent anti-inflammatory agent. After treatment, inflammation-associated mediators were effectively down-regulated, including NFkappaB, vascular endothelial growth factor (VEGF) and interleukin (IL)-6 as well as chemokines involved in MSC migration (CCL3 and CCL25). Treatment with the anti-inflammatory agent CDDO-Me before and after MSC-IFN-beta injections resulted in reduction of MSC in the tumors and reversed the positive effect of tumor inhibition by MSC-IFN-beta alone (P=0.041). Conclusions. These results suggest that MSC exhibit innate anti-tumor effects against PANC-1 cells and can serve as delivery vehicles for IFN-beta for the treatment of pancreatic cancer. However, these beneficial effects may be lost in therapies combining MSC with anti-inflammatory agents.

43: Expert opinion on biological therapy, 2010 Apr, 10(4)
Clinical effects and tolerability of high-dose, high-frequency recombinant interferon beta-1a in patients with multiple sclerosis: maximizing therapy through long-term adherence.

[Abstract]IMPORTANCE OF THE FIELD: High-dose, high-frequency IFN beta-1a in multiple sclerosis (MS) can prevent lesion formation, decrease the frequency/severity of relapses and delay progression of disability, with a proven safety profile. Rates of non-adherence are high. There are drugs under investigation that may have greater efficacy and different safety profiles from existing therapies. AREAS COVERED IN THIS REVIEW: Evidence supporting the efficacy of IFN beta-1a, factors contributing to non-adherence, and strategies to combat non-adherence. It is hoped that these strategies, coupled with future advances in pharmacogenetics, might lead to better outcomes. The PubMed database was searched using the terms "multiple sclerosis" and "interferon beta-1a", for papers published between 1998 and 2010. Relevant manuscripts and pivotal papers from clinical trials were cited. Searches of abstracts from congresses were also performed to obtain recent findings. WHAT THE READER WILL GAIN: An overview of early pivotal trials, comparative studies with other treatments, and recent studies assessing the development of this therapy. TAKE HOME MESSAGE: Long-term treatment with IFN beta-1a has benefits in MS and a good safety profile. Although adherence outside of clinical trials can be poor, injection devices, better tolerated drug formulations and education regarding treatment expectations are some of the strategies employed to help patients to adhere to treatment in the hope of improving outcomes.

44: Multiple sclerosis (Houndmills, Basingstoke, England), 2010 Mar 3, 201(6)
Rapid benefits of a new formulation of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis.

[Abstract]This study evaluated the efficacy of a new formulation of subcutaneous (sc) interferon (IFN)-beta1a in relapsing-remitting multiple sclerosis (RRMS). Patients (n = 180) were randomized (2 : 1) to IFN-beta1a or placebo for 16 weeks; all patients then received IFN-beta1a for 24 weeks. Monthly brain MRI was performed. At week 16, the mean number of combined unique active (CUA) lesions was lower with IFN-beta1a than with placebo (p < 0.001; 69% fewer lesions). The mean cumulative number of CUA lesions was already lower with IFN-beta1a by week 4 (post hoc analysis; p = 0.015). The new formulation of sc IFN-beta1a has rapid beneficial effects on MRI outcomes in RRMS.

45: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2010 Feb 28, 121(3)
Interleukin 7 Receptor Alpha Chain (IL-7Ralpha) Haplotypes Vary in Their Influence on Multiple Sclerosis Susceptibility and Response to Interferon Beta.

[Abstract]Interleukin 7 receptor alpha chain (IL-7Ralpha) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7Ralpha, and therefore reduced interference with receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 x 10(-10)), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7Ralpha proximal promoter contains response elements to interferon beta (IFN-beta), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7Ralpha is up-regulated in response to IFN-beta in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P < 0.002, n = 10) and homozygotes (trend only), and in CD4+CD45RO+ and CD4+CD45RA+ cells. In PBMCs, IL-7Ralpha cell surface protein (CD127) is lower in haplotype 4 carriers than non-carriers after incubation with IFN-beta (P < 0.003, n = 20). Response to IFN-beta includes viral protection and immune modulation, processes that could be pathogenically significant in MS. The haplotype-dependent variation in the regulation of IL-7Ralpha by IFN-beta may contribute to the genetic association of IL-7Ralpha with MS.

46: Inflammatory bowel diseases, 2010 Feb 23, 121(3)
Case series: Ulcerative colitis, multiple sclerosis, and interferon-beta 1a.

[Abstract]Interleukin 7 receptor alpha chain (IL-7Ralpha) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7Ralpha, and therefore reduced interference with receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 x 10(-10)), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7Ralpha proximal promoter contains response elements to interferon beta (IFN-beta), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7Ralpha is up-regulated in response to IFN-beta in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P < 0.002, n = 10) and homozygotes (trend only), and in CD4+CD45RO+ and CD4+CD45RA+ cells. In PBMCs, IL-7Ralpha cell surface protein (CD127) is lower in haplotype 4 carriers than non-carriers after incubation with IFN-beta (P < 0.003, n = 20). Response to IFN-beta includes viral protection and immune modulation, processes that could be pathogenically significant in MS. The haplotype-dependent variation in the regulation of IL-7Ralpha by IFN-beta may contribute to the genetic association of IL-7Ralpha with MS.

47: Neurology, 2010 Feb 23, 74(8)
Intramuscular interferon beta-1a in chronic inflammatory demyelinating polyradiculoneuropathy.

[Abstract]OBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shares immunologic features with multiple sclerosis (MS). Because IM interferon beta-1a (IM IFNbeta-1a) is an effective and safe treatment for MS, we conducted a dose-ranging efficacy study of IFNbeta-1a in patients with CIDP. METHODS: Adults with IV immunoglobulin (IVIg)-dependent CIDP (n = 67) were enrolled in this 32-week double-blind trial and randomized to IM IFNbeta-1a. Patients received 30 mug once weekly plus placebo (n = 12), IM IFNbeta-1a 60 mug once weekly plus placebo (n = 11), IM IFNbeta-1a 30 mug twice weekly (n = 11), IM IFNbeta-1a 60 mug twice weekly (n = 11), or placebo twice weekly (n = 22). Participants were maintained on IVIg through week 16, when IVIg was discontinued. Patients who worsened were restarted on IVIg. The primary outcome was total IVIg dose (g/kg) administered from week 16 to 32. RESULTS: There was no difference in total IVIg dose administered after week 16 for patients treated with IFNbeta-1a (1.20 g/kg) compared with placebo (1.34 g/kg; p = 0.75). However, exploratory analyses suggested IFNbeta-1a significantly reduced total dose of IVIg compared with placebo for participants who required either high-dose IVIg (>0.95 g/kg per month) or had greater weakness at baseline (Medical Research Council sum score <51). Adverse events included flu-like symptoms, headache, and fatigue in the IFNbeta-1a groups. CONCLUSIONS: Interferon beta-1a (IFNbeta-1a) therapy did not provide significant benefit over IV immunoglobulin (IVIg) therapy alone for patients with chronic inflammatory demyelinating polyradiculoneuropathy. However, IFNbeta-1a might be beneficial for patients with more severe disability or those needing high doses of IVIg. Level of evidence: This study was designed to provide Class I evidence for the safety and efficacy of IM IFNbeta-1a in the treatment of CIDP but has been subsequently classified as Class II due to a >20% patient dropout rate. Thus, this randomized, controlled clinical trial provides Class II evidence of no effect on primary and secondary endpoints of 4 dosage regimens of IM IFNbeta-1a added to IVIg in persons with CIDP.

48: Multiple sclerosis (Houndmills, Basingstoke, England), 2010 Feb 18, 74(8)
Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study.

[Abstract]Disease-modifying drugs are initiated early and continued for years in patients with multiple sclerosis. Long-term tolerability and impact are not known. The objective of this study was to evaluate long-term tolerability of intramuscular interferon beta-1a and effects on disability and quality of life. Patients were evaluated an average of 15 years after randomization into a placebo-controlled, double-blind trial of intramuscular interferon beta-1a for relapsing multiple sclerosis. Patient-reported Expanded Disability Status Scale, the Short Form-36, a visual analog scale of self-care independence, and a living situation questionnaire were administered. Status was ascertained in 79% (136/172) of eligible patients. Analysis focused on 122 living patients. Despite open-label, non-standardized treatment after the 2-year clinical trial, 46% (n = 56) of the patients remained on intramuscular interferon beta-1a. Expanded Disability Status Scale scores were correlated highly with Short Form-36 subcategories and visual analog scale scores. Patients currently using intramuscular interferon beta-1a had a significantly lower mean Expanded Disability Status Scale score (p = 0.011), less progression to Expanded Disability Status Scale milestones, significantly better scores on the physical component of the Short Form-36 (p < 0.0001), and reported better general health and greater independence. We conclude that patients continuing to use intramuscular interferon beta-1a had less disability and better quality of life compared with patients not currently using intramuscular interferon beta-1a 15 years after randomization into a clinical trial.

49: Biophysical journal, 2010 Feb 17, 98(4)
Immune Response Modeling of Interferon beta-Pretreated Influenza Virus-Infected Human Dendritic Cells.

[Abstract]The pretreatment of human dendritic cells with interferon-beta enhances their immune response to influenza virus infection. We measured the expression levels of several key players in that response over a period of 13 h both during pretreatment and after viral infection. Their activation profiles reflect the presence of both negative and positive feedback loops in interferon induction and interferon signaling pathway. Based on these measurements, we have developed a comprehensive computational model of cellular immune response that elucidates its mechanism and its dynamics in interferon-pretreated dendritic cells, and provides insights into the effects of duration and strength of pretreatment.

50: The Journal of infectious diseases, 2010 Mar 15, 201(6)
Interferon Beta modulates endothelial damage in patients with cardiac persistence of human parvovirus b19 infection.

[Abstract]Background. In a phase 1 study, we investigated whether interferon beta reduced endothelial damage in patients with cardiac persistence of human parvovirus B19 (B19V) infection. Methods and results. In vitro, B19V infected cultivated endothelial cells (ECs), which led to a reduction in their viability ([Formula: see text]). Interferon beta suppressed B19V replication by 63% ([Formula: see text]) in ECs and increased their viability ([Formula: see text]). Circulating mature apoptotic ECs (CMAECs [CD45(-)CD146(+) cells expressing von Willebrand factor and annexin V]) and circulating progenitor cells (CPCs [CD34(+)KDR(+) cells]) were quantified by flow cytometry in 9 symptomatic patients with cardiac B19V infection before and after 6 months of interferon beta therapy (16 MU) and were compared to levels in 9 healthy control subjects. Endothelial dysfunction was measured using flow-mediated dilatation of the forearm. Patients with B19V persistence had significantly higher ([Formula: see text]) levels of CMAECs than did control subjects, which normalized after treatment (mean +/- standard deviation, [Formula: see text] vs [Formula: see text]; [Formula: see text]). Similar improvement was shown for flow-mediated dilatation ([Formula: see text]) in the treatment group only ([Formula: see text] for the comparison with untreated patients with B19V persistence [[Formula: see text]]). There were significantly higher numbers of CPCs in patients with B19V persistence before therapy (mean +/- standard deviation, [Formula: see text] vs [Formula: see text]; [Formula: see text]) than in control subjects, which normalized after treatment ([Formula: see text]). Conclusion. Thus, we present (for the first time, to our knowledge) a modulation of virally induced chronic endothelial damage-specifically, EC apoptosis and endothelial regeneration.

51: Archives of neurology, 2010 Feb 8,
Clinical Effect of Neutralizing Antibodies to Interferon Beta That Persist Long After Cessation of Therapy for Multiple Sclerosis.

[Abstract]OBJECTIVES: To confirm that neutralizing antibodies (NAb) to interferon beta can persist after therapy withdrawal and to evaluate whether persisting NAb are associated with a worse clinical disease course in multiple sclerosis (MS). DESIGN: Retrospective study. SETTING: Tertiary referral center in the Netherlands.Patients A total of 71 patients with relapsing-remitting multiple sclerosis treated with interferon beta in the past. MAIN OUTCOME MEASURES: Persisting NAb after therapy withdrawal were tested using the cytopathic effect assay. Patients with and without persisting NAb were compared on several outcomes: the change in annualized relapse rate from prior to interferon beta treatment initiation to after cessation of treatment, time to sustained disability on the Kurtzke Expanded Disability Status Scale, and the use of disease-modifying treatments after cessation of treatment with interferon beta. RESULTS: Seventeen of 71 patients (24%) tested NAb positive after a median interval of 25 months (interquartile range, 10-51 months) after interferon beta treatment cessation. Eleven of these 17 patients (15%) were high-titer NAb positive (>150 10-fold reduction units per mL). Persisting NAb were associated with an increase in the annualized relapse rate (P = .04) and a reduction in time to reach a sustained Expanded Disability Status Scale score of 6.0, ie, the need for unilateral assistance to walk 100 m (P = .02). Moreover, NAb-positive patients were treated with second-line therapy significantly more often, especially mitoxantrone (P = .006). CONCLUSION: Anti-interferon beta NAb can persist after interferon beta treatment withdrawal and are associated with overt clinical disease activity. This is made apparent by an increase in relapse rate and faster disability progression and is supported by the observed need for more aggressive therapy after interferon beta treatment cessation. Prospective studies are warranted to confirm these results.Published online February 8, 2010 (doi: 10.1001/archneurol.2010.21).

52: Lung cancer (Amsterdam, Netherlands), 2010 Feb 4,
Human umbilical cord matrix-derived stem cells expressing interferon-beta gene significantly attenuate bronchioloalveolar carcinoma xenografts in SCID mice.

[Abstract]Mesenchymal stem cells derived from the human umbilical cord matrix (hUCMSCs) have great potential for therapeutic use for multiple diseases. The strategy that uses therapeutic gene-transfected hUCMSCs as cellular vehicles for targeted biologic agent delivery has solved the problem of short half-life or excessive toxicity of biological agent(s) in vivo. Interferon-beta (IFN-beta) has demonstrated a potent antitumor effect on many types of cancer cell lines in vivo. The aim of this study was to determine the anti-cancer effect of IFN-beta gene-transfected hUCMSCs (IFN-beta-hUCMSCs) on cells derived from bronchioloalveolar carcinoma, a subset of lung adenocarcinoma that is difficult to treat. The co-culture of a small number of IFN-beta-hUCMSCs with the human bronchioloalveolar carcinoma cell lines H358 or SW1573 significantly inhibited growth of both types of carcinoma cell lines. The culture medium conditioned by these cells also significantly attenuated the growth of both carcinoma cells, but this attenuation was abolished by adding anti-IFN-beta antibody. Finally, systemic administration of IFN-beta-hUCMSCs through the tail vein markedly attenuated growth of orthotopic H358 bronchioloalveolar carcinoma xenografts in SCID mice by increasing apoptosis. These results clearly indicate that IFN-beta-hUCMSCs caused cell death of bronchioloalveolar carcinoma cells through IFN-beta production, thereby attenuating tumor growth in vivo. These results indicate that IFN-beta-hUCMSCs are a powerful anti-cancer cytotherapeutic tool for bronchioloalveolar carcinoma.

53: Neurology, 2010 Feb 2, 74(5)
Encephalitis during interferon Beta-1a treatment in a child with optic neuritis.

[Abstract]Mesenchymal stem cells derived from the human umbilical cord matrix (hUCMSCs) have great potential for therapeutic use for multiple diseases. The strategy that uses therapeutic gene-transfected hUCMSCs as cellular vehicles for targeted biologic agent delivery has solved the problem of short half-life or excessive toxicity of biological agent(s) in vivo. Interferon-beta (IFN-beta) has demonstrated a potent antitumor effect on many types of cancer cell lines in vivo. The aim of this study was to determine the anti-cancer effect of IFN-beta gene-transfected hUCMSCs (IFN-beta-hUCMSCs) on cells derived from bronchioloalveolar carcinoma, a subset of lung adenocarcinoma that is difficult to treat. The co-culture of a small number of IFN-beta-hUCMSCs with the human bronchioloalveolar carcinoma cell lines H358 or SW1573 significantly inhibited growth of both types of carcinoma cell lines. The culture medium conditioned by these cells also significantly attenuated the growth of both carcinoma cells, but this attenuation was abolished by adding anti-IFN-beta antibody. Finally, systemic administration of IFN-beta-hUCMSCs through the tail vein markedly attenuated growth of orthotopic H358 bronchioloalveolar carcinoma xenografts in SCID mice by increasing apoptosis. These results clearly indicate that IFN-beta-hUCMSCs caused cell death of bronchioloalveolar carcinoma cells through IFN-beta production, thereby attenuating tumor growth in vivo. These results indicate that IFN-beta-hUCMSCs are a powerful anti-cancer cytotherapeutic tool for bronchioloalveolar carcinoma.

54: Arthritis and rheumatism, 2010 Jan 28, 62(2)
Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon-beta/alpha ratios in rheumatoid arthritis patients: A post hoc analysis of a predominantly Hispanic cohort.

[Abstract]OBJECTIVE: Despite the substantial clinical efficacy of tumor necrosis factor alpha (TNFalpha) antagonist therapy in patients with rheumatoid arthritis (RA), some patients respond poorly to such agents. Since an interferon (IFN) signature is variably expressed among RA patients, we investigated whether plasma type I IFN activity might predict the response to TNF antagonist therapy. METHODS: RA patients (n = 35), the majority of whom were Hispanic, from a single center were evaluated before and after initiation of TNF antagonist therapy. As controls, 12 RA patients from the same center who were not treated with a TNF antagonist were studied. Plasma type I IFN activity was measured using a reporter cell assay, and disease status was assessed using the Disease Activity Score in 28 joints (DAS28). Levels of interleukin-1 receptor antagonist (IL-1Ra) were determined in baseline plasma samples using a commercial enzyme-linked immunosorbent assay. The clinical response was classified according to the European League Against Rheumatism criteria for improvement in RA. RESULTS: Plasma type I IFN activity at baseline was significantly associated with clinical response (odds ratio 1.36 [95% confidence interval 1.05-1.76], P = 0.020), with high baseline IFN activity associated with a good response. Changes in DAS28 scores were greater among patients with a baseline plasma IFNbeta/alpha ratio >0.8 (indicating elevated plasma IFNbeta levels). Consistent with the capacity of IFNbeta to induce IL-1Ra, elevated baseline IL-1Ra levels were associated with better therapeutic outcomes (odds ratio 1.82 [95% confidence interval 1.1-3.29], P = 0.027). CONCLUSION: The plasma type I IFN activity, the IFNbeta/alpha ratio, and the IL-1Ra level were predictive of the therapeutic response in TNF antagonist-treated RA patients, indicating that these parameters might define clinically meaningful subgroups of RA patients with distinct responses to therapeutic agents.

55: Experimental neurology, 2010 Jan 26, 58(2)
PEGylated interferon-beta modulates the acute inflammatory response and recovery when combined with forced exercise following cervical spinal contusion injury.

[Abstract]Secondary degeneration leads to an expansion of the initial tissue damage sustained during a spinal cord injury (SCI). Dampening the cellular inflammatory response that contributes to this progressive tissue damage is one possible strategy for neuroprotection after acute SCI. We initially examined whether treatment with a PEGylated form of rat interferon-beta (IFN-beta) would modulate the expression of several markers of inflammation and neuroprotection at the site of a unilateral cervical level 5 contusion injury. Adult female Sprague-Dawley rats were injured using the Infinite Horizon Impactor at a force of 200Kdyne (equivalent to a severe injury) and a mean displacement of 1600-1800 microm. A single dose (5 x 10(6) units) of PEGylated IFN-beta or vehicle was administered 30 minutes following SCI. Here we demonstrate temporal changes in pro-and anti-inflammatory cytokine levels and the expression of heat shock proteins and iNOS (involved in neuroprotection) at the lesion epicenter and one segment caudally after SCI and PEG IFN-beta treatment. The results suggested a potential therapeutic treatment strategy for modulation of secondary damage after acute SCI. Therefore, we examined whether acute treatment with PEG IFN-beta would improve forelimb function alone or when combined with forced exercise (Ex). Animals began the Ex paradigm 5 days post SCI and continued for 5 days per week over 8 weeks. Locomotion (forelimb locomotor scale [FLS], hindlimb BBB, and TreadScan) and sensorimotor function (grid walking) was tested weekly. Additional outcome measures included lesion size and glial cell reactivity. Significant FLS improvements occurred at 1 week post SCI in the PEGylated IFN-beta-treated group but not at any other time point or with any other treatment approaches. These results suggest that this acute neuroprotective treatment strategy does not translate into long term behavioral recovery even when combined with forced exercise.

56: The Journal of biological chemistry, 2010 Mar 26, 285(13)
Virus-triggered Ubiquitination of TRAF3/6 by cIAP1/2 Is Essential for Induction of Interferon-{beta} (IFN-{beta}) and Cellular Antiviral Response.

[Abstract]Viral infection causes activation of transcription factors NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and cellular antiviral response. Here we show that knockdown of the E3 ubiquitin ligases cIAP1 and cIAP2 markedly inhibited virus-triggered activation of IRF3 and NF-kappaB as well as IFN-beta induction. Knockdown of cIAP1 and cIAP2 also inhibited cytoplasmic dsRNA-triggered cellular antiviral response. Endogenous coimmunoprecipitation experiments indicated that viral infection caused recruitment of cIAP1 and cIAP2 to TRAF3, TRAF6, and VISA. Furthermore, we demonstrated that cIAP1- and cIAP2-mediated virus-triggered ubiquitination of TRAF3 and TRAF6. These findings suggest that virus-triggered ubiquitination of TRAF3 and TRAF6 by cIAP1 and cIAP2 is essential for type I IFN induction and cellular antiviral response.

57: Annals of the New York Academy of Sciences, 2009 Dec, 1182(1)
Heterogeneous, longitudinally stable molecular signatures in response to interferon-beta.

[Abstract]Interferons (IFNs) are widely used in therapy for viral, neoplastic, and inflammatory disorders, but clinical response varies among patients. The biological basis for variable clinical response is not known. We determined the primary molecular response to IFN-beta (IFN-beta) injections in 35 treatment-na?ve multiple sclerosis (MS) patients using a customized cDNA macroarray with 186 interferon-stimulated genes (ISGs). Our results revealed striking interindividual heterogeneity, both in the magnitude as well as the nature of the primary molecular response to IFN-beta injections. Despite marked between-subject variability in the molecular response, responses within individual subjects were stable over a 6-month interval. Our data suggest that clinical response to IFN-beta therapy for MS differs among patients because of qualitative rather than quantitative variability in the primary molecular response to the drug.

58: Molecular therapy : the journal of the American Society of Gene Therapy, 2010 Jan 12, 285(3)
A Phase I Trial of Repeated Intrapleural Adenoviral-mediated Interferon-beta Gene Transfer for Mesothelioma and Metastatic Pleural Effusions.

[Abstract]We previously showed that a single intrapleural dose of an adenoviral vector expressing interferon-beta (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) or malignant pleural effusions (MPE) resulted in gene transfer, humoral antitumor immune responses, and anecdotal clinical responses manifested by modified Response Evaluation Criteria in Solid Tumors (RECIST) disease stability in 3 of 10 patients at 2 months and an additional patient with significant metabolic response on positron emission tomography (PET) imaging. This phase I trial was conducted to determine whether using two doses of Ad.IFN-beta vector would be superior. Ten patients with MPM and seven with MPE received two doses of Ad.IFN-beta through an indwelling pleural catheter. Repeated doses were generally well tolerated. High levels of IFN-beta were detected in pleural fluid after the first dose; however, only minimal levels were seen after the second dose of vector. Lack of expression correlated with the rapid induction of neutralizing Ad antibodies (Nabs). Antibody responses against tumor antigens were induced in most patients. At 2 months, modified RECIST responses were as follows: one partial response, two stable disease, nine progressive disease, and two nonmeasurable disease. One patient died after 1 month. By PET scanning, 2 patients had mixed responses and 11 had stable disease. There were seven patients with survival times longer than 18 months. This approach was safe, induced immune responses and disease stability. However, rapid development of Nabs prevented effective gene transfer after the second dose, even with a dose interval as short as 7 days.

59: Acta neurologica Scandinavica, 2010 Jan 6, 285(3)
Non-adherence to interferon-beta therapy in Swedish patients with multiple sclerosis.

[Abstract]Cunningham A, Gottberg K, von Koch L, Hillert J. Non-adherence to interferon-beta therapy in Swedish patients with multiple sclerosis. Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2009.01285.x. (c) 2009 The Authors Journal compilation (c) 2009 Blackwell Munksgaard. Objectives - To explore the occurrence and reasons for stopping, switching or continuing first prescribed interferon-beta therapy in patients with multiple sclerosis in Sweden, with respect to demographic, clinical and/or therapy-related factors. Materials and methods - A retrospective study reviewing the medical charts of 259 patients with multiple sclerosis, comparing patients continuing therapy for at least 3 years with those switching or stopping therapy. Results - Sixty 9% stopped (15%), or switched (54%), interferon-beta therapy within 3 years. Stoppers had longer disease duration before starting therapy (P = 0.002), less frequently relapsing-remitting multiple sclerosis (P = 0.046), and more often Expanded Disability Status Scale scores 6-9.5 (P = 0.045) compared to Switchers. The most common reasons for switching/stopping therapy were perceived lack of effect and side-effects. Conclusions - Adherence to initial immune-modulating therapy is low; identification of patients at higher risk of stopping therapy and provision of adequate support are essential.

60: European journal of neurology : the official journal of the European Federation of Neurological Societies, 2009 Dec 27, 16(1)
Neutralizing antibodies, MxA expression and MMP-9/TIMP-1 ratio as markers of bioavailability of interferon-beta treatment in multiple sclerosis patients: a two-year follow-up study.

[Abstract]Background: The objective of this study was to correlate the detection of neutralizing antibodies (NAbs) by the cytopathic effect (CPE) assay, with the expression of myxovirus resistance protein A (MxA), and the ratio between matrix metalloproteinase 9 (MMP-9) and its tissular inhibitor (TIMP-1), in order to evaluate their usefulness as markers of interferon beta (IFN-beta) bioavailability. Methods: Pairs of blood and serum samples were collected from 50 patients with multiple sclerosis (MS) during 2 years of IFN-beta treatment. Expression of MxA, MMP-9 and TIMP-1 were analysed by quantitative PCR, and NAbs were measured by CPE assay. Results: During the study, 60% of patients presented NAbs. The number of serum samples that were NAbs+ was significantly increased amongst patients with relapses (41/92 vs. 33/108, P = 0.04). With one serum sample and with a NAb titre >100 tenfold reduction unit (TRU), 66.7% of patients with MS suffered from relapses, 41.7% suffered from progression, and 75% was not an optimal clinical responder. We did not find any significant difference in MxA. We found that 62.5% of patients with MS patients whose ratio was increased twofold after 2 years suffered from relapses, 37.5% suffered from progression, and 68.7% was not an optimal clinical responder. Conclusion: The early detection of NAbs by CPE assay and the finding of only one serum sample with a NAb titre >100 TRU seem to be markers of low bioavailability of IFN-beta, whilst a twofold decrease in the MMP-9/TIMP-1 ratio by quantitative PCR assay seems to be a marker of high bioavailability of IFN-beta.

61: European journal of neurology : the official journal of the European Federation of Neurological Societies, 2009 Dec 27, 16(1)
Bioavailability of Interferon-beta in patients with multiple sclerosis - fishing for the surrogate.

[Abstract]Background: The objective of this study was to correlate the detection of neutralizing antibodies (NAbs) by the cytopathic effect (CPE) assay, with the expression of myxovirus resistance protein A (MxA), and the ratio between matrix metalloproteinase 9 (MMP-9) and its tissular inhibitor (TIMP-1), in order to evaluate their usefulness as markers of interferon beta (IFN-beta) bioavailability. Methods: Pairs of blood and serum samples were collected from 50 patients with multiple sclerosis (MS) during 2 years of IFN-beta treatment. Expression of MxA, MMP-9 and TIMP-1 were analysed by quantitative PCR, and NAbs were measured by CPE assay. Results: During the study, 60% of patients presented NAbs. The number of serum samples that were NAbs+ was significantly increased amongst patients with relapses (41/92 vs. 33/108, P = 0.04). With one serum sample and with a NAb titre >100 tenfold reduction unit (TRU), 66.7% of patients with MS suffered from relapses, 41.7% suffered from progression, and 75% was not an optimal clinical responder. We did not find any significant difference in MxA. We found that 62.5% of patients with MS patients whose ratio was increased twofold after 2 years suffered from relapses, 37.5% suffered from progression, and 68.7% was not an optimal clinical responder. Conclusion: The early detection of NAbs by CPE assay and the finding of only one serum sample with a NAb titre >100 TRU seem to be markers of low bioavailability of IFN-beta, whilst a twofold decrease in the MMP-9/TIMP-1 ratio by quantitative PCR assay seems to be a marker of high bioavailability of IFN-beta.

62: European journal of neurology : the official journal of the European Federation of Neurological Societies, 2009 Dec 21, 16(1)
Different responses to interferon beta-1b treatment in patients with neuromyelitis optica and multiple sclerosis.

[Abstract]Background: Although the benefit of treatment for relapsing-remitting multiple sclerosis (MS) is firmly established, whether interferon beta-1b (IFNB-1b) therapy is efficacious for neuromyelitis optica (NMO) has been debated. Methods: We reviewed the responses to IFNB-1b treatment in 18 patients with relapsing NMO and compared the results with those from 38 patients with relapsing-remitting MS. We compared clinical characteristics, the annualized relapse rate (ARR) and the probability of being relapse free before and after IFNB-1b treatment in patients with NMO and MS. Results: The proportion of patients with more than 50% increase in the ARR after IFNB-1b treatment was much higher in NMO than in MS (P = 0.046). ARR was significantly lower in patients with MS after IFNB-1b administration than before (P = 0.015), but not in NMO. Kaplan-Meier and log-rank statistical analyses revealed that relapse-free rates were lower in NMO than MS after IFNB-1b treatment (P = 0.032). The analyses also showed lower relapse-free rates during the pre-IFNB-1b treatment period than the post-IFNB-1b treatment period in MS (P < 0.001), but not in NMO. Conclusion: IFNB-1b treatment does not appear to be effective for preventing relapse in NMO likely because of differences between the immune-pathogenesis of NMO and MS.

63: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2009 Dec 28, 16(1)
STAT-Phosphorylation-Independent Induction of Interferon Regulatory Factor-9 by Interferon-beta.

[Abstract]Type I interferon (IFN)-dependent STAT1 and STAT2 activation requires specific tyrosine residues (337Y and 512Y) located in the cytoplasmic domain of IFNAR-2c, the beta-subunit of the human type I IFN receptor. To identify STAT activation-independent induction of ISGs, we used a mutant cell line in which both 337Y and 512Y were substituted with phenylalanine (337F512F or FF mutant). In these cells, type I IFN failed to activate STAT1, STAT2, and STAT3 did not induce well-characterized ISGs and did not exert antiviral or antiproliferative effects. Using Oligonucleotide array (Affymetrix) analysis, we showed that interferon regulatory factor-9 (IRF-9) was the only gene induced by IFN-beta in FF cells. Transient transfection analysis using an IRF-9 promoter-reporter luciferase construct in FF cells confirmed induction of the IRF-9 transcription unit by IFN-beta. EMSA analysis using an IFN-stimulated response element (ISRE)-like sequence on the IRF-9 promoter detected 2 novel DNA-binding complexes induced in nuclear extracts of IFN-beta-treated FF cells. Supershift experiments identified the proteins IRF-1 and C/EBP-beta in the complex. These studies provide the first evidence that signaling pathways leading to gene transcription are activated by IFN-beta independent of STAT phosphorylation.

64: Journal of agricultural and food chemistry, 2009 Dec 23, 16(1)
Isoegomaketone Inhibits Lipopolysaccharide-Induced Nitric Oxide Production in RAW 264.7 Macrophages through the Heme Oxygenase-1 Induction and Inhibition of the Interferon-beta-STAT-1 Pathway.

[Abstract]Isoegomaketone (IK) is an essential oil component of Perilla frutescens (L.) Britt., and there have been no studies investigating its biological activities. We found that IK inhibits lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages, and moreover, when IK was injected into animals prior to LPS administration, NO serum levels decreased in a dose-dependent manner. These results indicate that IK possesses anti-inflammatory activity both in vitro and in vivo. IK suppressed the phosphorylation of STAT-1 and the production of IFN-beta. Treatment with IK also inhibited the activation of NF-kappaB and activator protein-1, but more IK was required for inhibition than for STAT-1 inhibition, indicating that downregulation of inducible nitric oxide synthase gene expression by IK is mainly attributed to the blockade of STAT-1 activation. Furthermore, IK also induced the expression of heme oxygenase-1 (HO-1) through the activation of nuclear factor E2-related factor 2. Treatment with SnPP, a selective inhibitor of HO-1, reversed the IK-induced suppression of STAT-1 phosphorylation and NO production. Taken together, IK isolated from P. frutescens inhibits NO production in LPS-treated RAW 264.7 macrophages through simultaneous induction of HO-1 and inhibition of the IFN-beta-STAT-1 pathway.

65: Multiple sclerosis (Houndmills, Basingstoke, England), 2010 Jan, 16(1)
Immunoglobulin-like transcript 3, an inhibitor of T cell activation, is reduced on blood monocytes during multiple sclerosis relapses and is induced by interferon beta-1b.

[Abstract]Immunoglobulin-like transcripts (ILTs) are immunoregulatory proteins that either activate or inhibit immune responses. ILT3 is inhibitory and is expressed preferentially by antigen-presenting cells. When its extracellular domain binds to an unidentified ligand of activated T cells, the T cell is silenced. Our objective was to study the expression of ILT3 on circulating monocytes in RRMS. Freshly isolated peripheral blood mononuclear cells were analyzed by multicolored flow cytometry. The proportion of ILT3(+)CD14(+) monocytes in blood, and ILT3 levels expressed by them, is lower in untreated multiple sclerosis in relapse than in: (1) untreated multiple sclerosis in remission (p < 0.009); (2) stable interferon beta-treated relapsing-remitting multiple sclerosis (p < 0.001) and; (3) healthy controls (p < 0.009). Glatiramer acetate-stimulated CD4( +) T cells, co-cultured with freshly isolated monocytes, proliferate significantly better (p = 0.0017 for multiple sclerosis; p = 0.0015 for controls) when T cell interaction with monocyte-expressed ILT3 is blocked by anti-ILT3 antibody. Interferon beta is beneficial in multiple sclerosis; why so remains unclear. Interferon beta-1b markedly increases ILT3 expression in vitro by monocytes from multiple sclerosis patients and controls. These findings identify a putative novel mechanism for the therapeutic benefit bestowed by Interferon beta and a new target for therapeutic intervention in relapsing-remitting multiple sclerosis.

66: Trials, 2009, 10(1)
SWiss Atorvastatin and interferon Beta-1b trial In Multiple Sclerosis (SWABIMS)--rationale, design and methodology.

[Abstract]BACKGROUND: Statins have anti-inflammatory and immunomodulatory properties in addition to their lipid-lowering effects. Currently, the effects of statins on multiple sclerosis are still controversial. Therefore, randomized clinical trials are needed to provide better evidence on the therapeutic potential of statins in multiple sclerosis. The SWiss Atorvastatin and Interferon Beta-1b trial in Multiple Sclerosis (SWABIMS) evaluates the efficacy, safety and tolerability of atorvastatin 40 mg per os daily and subcutaneous interferon beta-1b every other day compared to monotherapy with subcutaneous interferon beta-1b every other day in patients with relapsing-remitting multiple sclerosis. METHODS/DESIGN: SWABIMS is a multi-centre, randomized, parallel-group, rater-blinded, Phase IIb-study conducted in eight hospitals in Switzerland. 80 treatment na?ve patients with relapsing-remitting forms of multiple sclerosis will receive subcutaneous interferon beta-1b for three months. Afterwards, they are randomized into two equal-sized parallel arms, receiving atorvastatin 40 mg/d or not in addition to interferon beta-1b for another 12 months. Disease activity measured by the proportion of patients with new T2 lesions is the primary endpoint. DISCUSSION: SWABIMS is designed to give further information about the therapeutic effect of atorvastatin 40 mg per os daily as add-on therapy to interferon beta-1b in patients with relapsing-remitting multiple sclerosis. Furthermore important safety and tolerability data will be generated. TRIAL REGISTRATION: http://www.clinicaltrials.gov. Identifier: NCT00942591; Swissmedic reference number: 2005DR2119.

67: Multiple sclerosis (Houndmills, Basingstoke, England), 2009 Nov 13, 286(1-2)
Influence of interferon-beta therapy switching on neutralising antibody titres: results from the Austrian Switch Study (ASS).

[Abstract]Neutralizing antibodies against interferon-beta are associated with a reduction of the efficacy of this drug. Continuing treatment leads to a decline or even loss of neutralizing antibodies over years. No strategies are currently available to shorten the period of neutralizing antibody positivity. The objective of this study was to investigate the effect of switching between high and low immunogenic interferon-beta products on neutralising antibody titres. Twenty-four patients treated with the subcutaneously administered interferon-beta 1b or 1a and high titres of neutralizing antibodies were included. At baseline interferon-beta therapy was interrupted for 3 months and two pulses of high dose methylprednisolone were applied. Patients were then randomized to receive either the previous interferon-beta preparation or the low immunogenic intramuscular interferon-beta 1a. The primary end-point was the change of neutralizing antibody titres 12 months after randomization. Twelve patients were switched to interferon-beta 1a intramuscularly and 12 patients remained on previous treatment. Median neutralizing antibody titres were 846 NU at baseline and 196 NU at the end of the study. The median change of neutralizing antibody titres did not differ significantly between therapy switchers and non-switchers. Baseline and final neutralizing antibody titres correlated significantly. In conclusion, neither switching nor continuous therapy with any subcutaneous interferon-beta preparation significantly changed neutralizing antibody titres.

68: The Journal of biological chemistry, 2010 Jan 22, 285(4)
Regulation of SIVmac239 Basal Long Terminal Repeat Activity and Viral Replication in Macrophages: FUNCTIONAL ROLES OF TWO CCAAT/ENHANCER-BINDING PROTEIN {beta} SITES IN ACTIVATION AND INTERFERON {beta}-MEDIATED SUPPRESSION.

[Abstract]CCAAT/enhancer-binding protein (C/EBP) beta and C/EBP sites in the HIV-1 long terminal repeat (LTR) are crucial for HIV-1 replication in monocyte/macrophages and for the ability of interferon beta (IFNbeta) to inhibit ongoing active HIV replication in these cells. This IFNbeta-mediated down-regulation involves induction of the truncated, dominant-negative isoform of C/EBPbeta referred to as liver-enriched transcriptional inhibitory protein (LIP). Although binding of the C/EBPbeta isoform to C/EBP sites in the simian immunodeficiency virus (SIV) LTR has previously been examined, the importance of these sites in core promoter-mediated transcription, virus replication, IFNbeta-mediated regulation, and the relative binding of the two isoforms (C/EBPbeta and LIP) has not been investigated. Here, we specifically examine two C/EBP sites, JC1 (-100 bp) and DS1 (+134 bp), located within the minimal region of the SIV LTR, required for core promoter-mediated transcription and virus replication in macrophages. Our studies revealed that the JC1 but not DS1 C/EBP site is important for basal level transcription, whereas the DS1 C/EBP site is imperative for productive virus replication in primary macrophages. In contrast, either JC1 or DS1 C/EBP site is sufficient to mediate IFNbeta-induced down-regulation of SIV LTR activity and virus replication in these cells. We also characterized the differential binding properties of C/EBPbeta and LIP to the JC1 and DS1 sites. In conjunction with previous studies from our laboratory, we demonstrate the importance of these sites in virus gene expression, and we propose a model for their role in establishing latency and persistence in macrophages in the brain.

69: Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2009 Nov 19, 146(1-2)
Psoriasis during interferon beta treatment for multiple sclerosis.

[Abstract]Previous reports have suggested an increased risk of psoriasis in MS patients. Worsening of dermatologic lesions during interferon therapy has been rarely reported, but activation of psoriatic arthritis has not been described until now. The following is a case report. A 37-year-old woman affected by relapsing-remitting multiple sclerosis had severe worsening of cutaneous psoriasis and activation of psoriatic arthritis during interferon beta treatment. The symptoms resolved after therapy discontinuation. This case further supports that activation of psoriasis might be a rare side effect of IFNB therapy and suggests careful evaluation of concomitant morbidity to allow a patient-oriented treatment strategy.

70: Acta neurologica Scandinavica, 2009 Dec, 120(6)
Stroke after initiation of interferon-beta treatment for relapsing-remitting disseminated white matter disease.

[Abstract]

71: Human gene therapy, 2009 Nov 13, 286(1-2)
Safety Studies on Intrahepatic or Intratumoral Injection of Oncolytic Vesicular Stomatitis Virus Expressing Interferon-Beta in Rodents and Nonhuman Primates.

[Abstract]Toxicology studies were performed in rats and rhesus macaques to establish a safe starting dose for intratumoral injection of an oncolytic vesicular stomatitis virus expressing human interferon-beta (VSV-hIFNbeta) in patients with hepatocellular carcinoma (HCC). No adverse events were observed after administration of 7.59x109 TCID50 VSV-hIFNbeta into the left lateral hepatic lobe of Harlan Sprague Dawley rats. Plasma alanine aminotransferase and alkaline phosphatase levels increased and platelet counts decreased in the virus treated animals on days 1 and 2 but returned to pre-treatment levels by day 4. VSV-hIFNbeta was also injected into normal livers or an intrahepatic McA-RH7777 HCC xenograft established in Buffalo rats. Buffalo rats were more sensitive to neurotoxic effects of VSV; the no observable adverse event level (NOAEL) of VSV-hIFNbeta in Buffalo rats was 10e7 TCID50. Higher doses were associated with fatal neurotoxicity and infectious virus was recovered from tumor and brain. Compared to VSV-hIFNbeta, toxicity of VSV-rIFNbeta (recombinant VSV expressing rat IFNbeta) was greatly diminished in Buffalo rats (NOAEL >10e10 TCID50). Two groups of two adult male Rhesus macaques received 10e9 or 10e10 TCID50 VSV-hIFNbeta injected directly into the left hepatic lobe under CT guidance. No neurological signs were observed at any time point. No abnormalities (hematology, clinical chemistry, body weights, behavior) were seen and all macaques developed neutralizing anti-VSV antibodies. Plasma IL-6, TNF-alpha and hIFNbbeta remained below detection levels by ELISA. Based on these studies, we will be proposing a cautious approach to dose escalation in a phase I clinical trial among patients with HCC.

72: The Journal of biological chemistry, 2010 Jan 15, 285(3)
Cannabinoids Delta(9)-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-beta/STAT proinflammatory pathways in BV-2 microglial cells.

[Abstract]Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. However, the mechanisms of these effects are not completely understood. Using the BV-2 mouse microglial cell line and lipopolysaccharide (LPS) to induce an inflammatory response, we studied the signaling pathways engaged in the anti-inflammatory effects of cannabinoids as well as their influence on the expression of several genes known to be involved in inflammation. We found that the two major cannabinoids present in marijuana, Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), decrease the production and release of proinflammatory cytokines, including interleukin-1beta, interleukin-6, and interferon (IFN)beta, from LPS-activated microglial cells. The cannabinoid anti-inflammatory action does not seem to involve the CB1 and CB2 cannabinoid receptors or the abn-CBD-sensitive receptors. In addition, we found that THC and CBD act through different, although partially overlapping, mechanisms. CBD, but not THC, reduces the activity of the NF-kappaB pathway, a primary pathway regulating the expression of proinflammatory genes. Moreover, CBD, but not THC, up-regulates the activation of the STAT3 transcription factor, an element of homeostatic mechanism(s) inducing anti-inflammatory events. Following CBD treatment, but less so with THC, we observed a decreased level of mRNA for the Socs3 gene, a main negative regulator of STATs and particularly of STAT3. However, both CBD and THC decreased the activation of the LPS-induced STAT1 transcription factor, a key player in IFNbeta-dependent proinflammatory processes. In summary, our observations show that CBD and THC vary in their effects on the anti-inflammatory pathways, including the NF-kappaB and IFNbeta-dependent pathways.

73: Lancet neurology, 2009 Dec, 8(12)
Do interferon beta-1b and glatiramer acetate grow brain?

[Abstract]

74: The Journal of general virology, 2009 Nov 11, 286(1-2)
Interferon beta plus gamma efficiently reduces acyclovir-resistant herpes simplex virus infection in mice in a T-cell-independent manner.

[Abstract]Acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) causes severe diseases in immunocompromised patients, so identification of new therapies is needed. Interferons (IFNs) are used to treat several other viral infections in the clinic, and IFN-gamma and IFN-beta are shown to cooperatively reduce wild-type HSV-1 replication in the corneas of immunocompetent mice. Because IFN-gamma is shown to exert antiviral effect mostly through T cells, whether combined IFN treatment could still inhibit ACV-resistant HSV-1 replication, especially in imunocompromised hosts, is unknown. In the present study, we evaluated the efficacy of combined IFN treatment on ACV-resistant HSV-1 mutants. In vitro results showed that IFN-beta synergized with IFN-gamma to inhibit HSV-1 replication in both human and mouse cell lines. Some ACV-resistant mutants were actually hypersensitive to combined IFN treatment. In vivo results showed that topical treatment with a low dose of IFN-beta plus IFN-gamma (200 U each) on mouse corneas efficiently reduced the viral loads up to 4, 4, and 3 logs, respectively in the eyes, trigeminal ganglia, and brain stems of wild-type and also immunocompromised, nude mice infected or co-infected with ACV-resistant HSV-1 in a manner independent of T cells. Highly efficient reduction of HSV acute replication by combined IFN treatment led to a dramatic decrease in subsequent viral reactivation from neural tissues, trigeminal ganglia, brain stems, and spinal cords of latently infected mice. Thus, combination of IFN-beta and IFN-gamma could be a potential treatment for ACV-resistant HSV-1 in immunocompromised patients.

75: Cancer gene therapy, 2009 Nov 6, 286(1-2)
Genetic immunotherapy of lung cancer using conditionally replicating adenovirus and adenovirus-interferon-beta.

[Abstract]Genetic immunotherapy is considered an ideal treatment modality for cancer because of its systemic nature. This study was designed to develop a potent novel genetic immunotherapy by combining conditionally replicating adenovirus (CRAd) and replication-defective adenovirus expressing interferon-beta (ad-IFN-beta). We investigated the efficacy of this therapy in an immunocompetent mouse tumor model. Transduction with CRAd (Delta24RGD) induced cytolysis in a mouse lung cancer cell line (Lewis lung carcinoma (LLC)). Combined transduction of ad-IFN-beta and Delta24RGD in the LLC cells induced a greater and more prolonged production of IFN-beta. Media transfer from the LLC-Delta24RGD-ad-IFN-beta to untransduced LLC cells induced the production of IFN-beta; these results confirmed the replication and release of ad-IFN-beta. LLC cells transduced with ad-IFN-beta and Delta24RGD had decreased tumorigenicity in syngeneic mice. Tumor vaccination with irradiated LLC-ad-IFN-beta-Delta24RGD showed a significant increase in the survival of tumor-bearing syngeneic mice compared with mice with a single transduced LLC vaccination; this was mediated by an enhanced cytotoxic T-lymphocyte response against the LLC cells. The results of this study showed that cotransduced Delta24RGD to ad-IFN-beta aided the replication of ad-IFN-beta in the LLC cells. A high local concentration of IFN-beta and local release of tumor antigen by CRAd induced strong antitumor immunity. This combination strategy might provide a powerful means by which ad-cytokines and CRAd can be combined and other adenoviruses expressing different cytokines might also be used.Cancer Gene Therapy advance online publication, 6 November 2009; doi:10.1038/cgt.2009.78.

76: Neurology, 2009 Nov 3, 73(18)
Effect of neutralizing antibodies on biomarker responses to interferon beta: the INSIGHT study.

[Abstract]BACKGROUND: Interferon beta (IFNbeta) effectively reduces disease activity in patients with multiple sclerosis (MS). Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNbeta therapies. Biomarkers of the IFNbeta response, such as myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), may be used to measure the in vivo effects of NAbs on IFNbeta bioactivity. METHODS: In this multicenter, open-label study, antibody status was measured at screening, and then antibody status, levels of MxA, viperin, and IFIT-1 were measured at baseline (< or =8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNbeta-1a, subcutaneous (SC) IFNbeta-1a, or IFNbeta-1b. RESULTS: Treatment with IM IFNbeta-1a was associated with a lower rate of NAb formation among 718 patients screened (p < 0.0001 vs SC IFNbeta-1a 22 microg, 44 microg, and IFNbeta-1b). At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb-)/NAb-negative (NAb-) patients (all p < 0.0001). Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titers > or =100 TRU compared with BAb-/NAb- patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and biomarker responses remained consistently depressed in these patients at month 6. CONCLUSIONS: These data provide evidence that high titers of neutralizing antibodies abolish the in vivo response to interferon beta.

77: Journal of immunological methods, 2009 Oct 23, 215(1-2)
Hybrid transgenic immune tolerant mouse model for assessing the breaking of B cell tolerance by human interferon beta.

[Abstract]To date, the therapeutic efficacy of recombinant human proteins is limited by their potential to break B cell tolerance in patients. The formation of neutralising antibodies (NABs) directed against recombinant human interferon beta (rhIFNbeta) is associated with a decrease in the therapeutic effect of the protein. For this reason, there is a need to study factors that can cause the immunogenicity of rhIFNbeta. Transgenic C57Bl/6 mice that are immune tolerant for human interferon beta (hIFNbeta) have been employed in a mouse model for assessing the breaking of immune tolerance by rhIFNbeta. In this study, we used the original C57Bl/6 mouse model as well as the hybrid offspring from crossings of transgenic C57Bl/6 mice with wildtype FVB/N mice to study the immunogenicity of three commercial rhIFNbeta products, Rebif(R), Avonex(R) and Betaferon(R). As determined by ELISA, wildtype C57Bl/6 mice failed to form binding antibodies (BABs) against Rebif(R) and Avonex(R) formulated with human serum albumin. Because not all interferon beta products induce antibodies in wildtype C57Bl/6 mice, the transgenic C57Bl/6 mice cannot be used to study the breaking of tolerance by these products. However, the crossing of transgenic C57Bl/6 mice with FVB/N mice resulted in wildtype hybrid offspring in which all products were immunogenic and transgenic hybrid offspring that showed immune tolerance for hIFNbeta. Thus, these C57Bl/6 x FVB/N hybrid transgenic mice can be used to study the breaking of immune tolerance for all rhIFNbeta products. Of the three products, only Betaferon(R) was able to break immune tolerance in the transgenic hybrids. With an MxA gene expression inhibition assay, NABs were detected in Betaferon(R) treated wildtype hybrid mice, but not in transgenic hybrid mice, indicating a distinct immune mechanism in wildtype and transgenic mice. A pegylated rhIFNbeta-1a variant, PEG-rhIFNbeta-1a, induced antibodies in wildtype hybrid mice, but did not break the immune tolerance of transgenic hybrid mice. This suggests that pegylation did not affect the potential of rhIFNbeta-1a to break B cell tolerance.

78: Journal of virology, 2009 Oct 21, 215(1-2)
Mechanisms of Protein Kinase PKR-mediated Amplification of Interferon Beta Induction by C Protein-deficient Measles Virus.

[Abstract]The measles virus P gene products V and C antagonize the host interferon (IFN) response, blocking both IFN signaling and production. Using Moraten vaccine strain-derived measles virus and isogenic mutants deficient for either V or C protein production (V(ko) and C(ko), respectively), we observed that the C(ko) virus was a potent inducer of IFN-beta while induction by V(ko) virus was an order of magnitude lower than the C(ko) virus. The parental recombinant Moraten virus did not significantly induce IFN-beta. The enhanced IFN inducing capacity of the C(ko) virus correlated with enhanced activation of IRF-3, NF-kappaB and ATF-2 in C(ko)-infected compared to V(ko) or parental virus-infected cells. Furthermore, protein kinase PKR and mitochondrial adapter IPS-1 were required for maximal C(ko)-mediated IFN-beta induction, which correlated with PKR-mediated enhancement of MAP kinase and NF-kappaB activation. Our results reveal multiple consequences of C protein expression, and document an important function for PKR as an enhancer of IFN-beta induction during measles virus infection.

79: BMC neurology, 2009 Oct 13, 9(1)
Neutralizing antibodies explain the poor clinical response to Interferon beta in a small proportion of patients with Multiple Sclerosis: a retrospective study.

[Abstract]ABSTRACT: BACKGROUND: Neutralizing antibodies (NAbs) against Interferon beta (IFNbeta) are reported to be associated with poor clinical response to therapy in multiple sclerosis (MS) patients. We aimed to quantify the contribution of NAbs to the sub-optimal response of IFNbeta treatment. METHODS: We studied the prevalence of NAbs in MS patients grouped according to their clinical response to IFNbeta during the treatment period. Patients were classified as: group A, developing [greater than or equal to]1 relapse after the first 6 months of therapy; group B, exhibiting confirmed disability progression after the first 6 months of therapy, with or without superimposed relapses; group C, presenting a stable disease course during therapy. A cytopathic effect assay tested the presence of NAbs in a cohort of ambulatory MS patients treated with one of the available IFNbeta formulations for at least one year. NAbs positivity was defined as NAbs titre [greater than or equal to]20 TRU. RESULTS: Seventeen patients (12.1%) were NAbs positive. NAbs positivity correlated with poorer clinical response (p<0.04). As expected, the prevalence of NAbs was significantly lower in Group C (2.1%) than in Group A (17.0%) and Group B (17.0%). However, in the groups of patients with a poor clinical response (A, B), NAbs positivity was found only in a small proportion of patients. CONCLUSIONS: The majority of patients with poor clinical response are NAbs negative suggesting that NAbs explains only partially the sub-optimal response to IFNbeta.

80: Archives of neurology, 2009 Oct, 66(10)
Immunotherapy for multiple sclerosis: the curious case of interferon beta.

[Abstract]BACKGROUND: To evaluate the clinical effect of interferon beta-1a on optic neuritis (ON) relapse in patients with multiple sclerosis (MS) in Taiwan. METHODS: Data were collected from 23 MS patients with ON at National Taiwan University Hospital between January 1, 1993 and February 1, 2007. Twenty-three MS patients with ON received interferon beta-1a (Rebif) 44 microg via subcutaneous injection three times weekly. All patients received corticosteroids pulse therapy followed by oral prednisolone for acute ON. The annual relapse rate (ARR) of ON in these MS patients before and after the use of interferon beta-1a (Rebif) was the main clinical parameter of outcome in this study. RESULTS: The ARR of ON was lower in the posttreatment period than in the pretreatment period (P = 0.0068). Thirteen patients (56.5%) had improved final visual acuity (>2 lines), and the other ten patients (43.5%) had stable final visual outcome (-2 lines < X < 2 lines). In addition, no recurrence of ON was noted in 15 patients (65.2%) during the posttreatment period. CONCLUSIONS: The use of interferon beta-1a 44 microg via subcutaneous injection three times weekly did not increase the ON attacks in MS patients receiving this treatment. In addition, beneficial effects were found with the use of interferon beta-1a on these patients.

81: The Journal of general virology, 2009 Sep 30, 8(10)
Expression of the NS3 protease of cytopathogenic BVDV results in the induction of apoptosis but does not block activation of the interferon beta promoter.

[Abstract]The Pestivirus, Bovine Viral Diarrhoea Virus (BVDV), can exist as two biotypes, cytopathogenic (cp) and non-cytopathogenic (ncp). The cp differs from ncp by the continual expression of free non-structural protein 3 (NS3). Cp BVDV infection of cultured cells induces apoptosis, whereas ncp BVDV infection has been reported to block the induction of IFN-beta. To investigate the viral mechanisms underlying these effects NS3 or NS2-3 proteins of ncp and cp BVDV biotypes, together with the cognate NS3 cofactor NS4A, were expressed in cells and their effect upon apoptosis and induction of IFN-beta was investigated. Expression of NS3/4A resulted in increased activity of caspase 9 and caspase 3, indicating the induction of the intrinsic apoptosis pathway. Mutational analysis revealed that a protease inactive NS3/4A was unable to induce apoptosis suggesting that the NS3 protease activity is required for initiation of apoptosis during cp BVDV infection. The ability of NS2-3 to modulate activation of the IFN-beta promoter was also investigated. These studies confirmed that, unlike the related viruses HCV and GBV-B, the BVDV proteases are unable to inhibit TLR3 and RIG-I dependent activation of the IFNbeta promoter. These data suggest that BVDV NS3/4A is responsible for regulating the levels of cellular apoptosis and provide new insights regarding the viral elements associated with cp biotype pathogenesis.

82: Virus research, 2009 Dec, 146(1-2)
Glycosylation of classical swine fever virus E(rns) is essential for binding double-stranded RNA and preventing interferon-beta induction.

[Abstract]Host cells sense double-stranded RNA (dsRNA) produced during viral replication and initiate type I interferon (IFN-alpha/beta) production, leading to subsequent antiviral responses. Many viruses, including classical swine fever virus (CSFV), have developed strategies for counteracting the IFN-alpha/beta response. In this study, we explored the role of the CSFV E(rns) glycoprotein in the inhibition of IFN-beta production induced by dsRNA [poly(IC)]. Our results demonstrated that CSFV E(rns) could bind to exogenous dsRNA and inhibit dsRNA-induced IFN-beta production but failed to inhibit TRIF-triggered IFN-beta production. Our data suggest that the inhibition of IFN-beta induction occurred at the initial step of the TLR3 signaling pathway. We also showed that deglycosylation of E(rns) rendered it unable to bind to dsRNA, and thus unable to inhibit dsRNA-induced IFN-beta production. Taken together, these results indicated that N-glycan of CSFV E(rns) is essential for E(rns) blocking of IFN-beta induction.

83: Journal of neuroimmunology, 2009 Oct 30, 215(1-2)
Interferon-beta therapy for multiple sclerosis - is the injection site the relevant action site?

[Abstract]Multiple sclerosis (MS) has been characterized as a T cell-mediated autoimmune disease. Recent research on the immunopathology of MS has implicated dendritic cells, professional antigen-presenting cells essential for T cell differentiation and proliferation of self-reactive T cells. Interferon-beta therapy effectively reduces relapse rates in MS and can slow the progression of disability in patients with relapsing-remitting MS. The principal mechanism by which interferon-beta drugs exert their effect is unclear; however, it is possible that an interaction with dendritic cells local to the site of injection may be critical. Most subcutaneously administered interferon-beta never leaves the injection site. This article reviews current concepts on the immunopathogenesis of MS and presents the hypothesis that the main effect of interferon-beta in MS is mediated by local effects on dendritic cells at the injection site.

84: Journal of neuroimmunology, 2009 Oct 30, 215(1-2)
Effects of interferon-beta therapy on innate and adaptive immune responses to the human endogenous retroviruses HERV-H and HERV-W, cytokine production, and the lectin complement activation pathway in multiple sclerosis.

[Abstract]The effects of treatment of multiple sclerosis patients with IFN-beta on elements in the innate and adaptive immune response were analysed in a longitudinal study. We demonstrate significant decreases in anti-Envelope antibody reactivity for the two closely related Gammaretroviral human endogenous retroviruses (HERVs), HERV-H and HERV-W, as a consequence of IFN-beta therapy, closely linked to efficacy of therapy/low disease activity. We also show strong indications of a protective effect of high levels of two components in the innate pathogen-associated molecular pattern recognition: mannan-binding lectin (MBL), and MBL-associated serine protease 3 (MASP-3). Serum levels of typical Th1- and Th2-related, MS-relevant cytokines were also monitored. Overall both Th1- and Th2-associated cytokines were modestly, albeit significantly up-regulated, notably IL-2 and TNF-alpha (MS patients with inactive disease), as well as IL-4 and, to some extent IL-10 (no increase in IL-10 for MS patients with active disease (non-responders)). We found no overall changes in Th1/Th2 ratios. Our results support that HERV-H/HERV-W and the antiviral immune response may play a role in MS development, and that these HERVs have potential as biomarkers for disease activity.

85: Journal of neuroimmunology, 2009 Oct 30, 215(1-2)
Interferon-beta-1a treatment increases CD56(bright) natural killer cells and CD4+CD25+ Foxp3 expression in subjects with multiple sclerosis.

[Abstract]Disease modifying effects of interferon (IFN)-beta therapy in patients with multiple sclerosis (MS) may be mediated in part through enhanced immunoregulation by the CD56(bright) subpopulation of natural killer (NK) cells and by Foxp3+ (not italicized) CD4+CD25+ regulatory T cells (Treg). We found that IFN-beta-1a(IM) treatment of relapsing-remitting (RR)MS subjects over 12 months significantly increased both percentage of CD56(bright) NK cells and Foxp3 mRNA expression compared to baseline values, untreated RRMS subjects and healthy controls (HC). This striking enhancement of two prominent immunoregulatory pathways lends support to the idea that beneficial effects of IFN-beta-1a in MS include control of pernicious autoimmunity.

86: Lancet neurology, 2009 Nov, 8(11)
Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial.

[Abstract]BACKGROUND: The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. METHODS: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 mug (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211. FINDINGS: 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0.63, 95% CI 0.48-0.83; p=0.003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0.76, 0.52-1.11; p=0.177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b. INTERPRETATION: Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes. FUNDING: Bayer Schering Pharma.

87: Brain : a journal of neurology, 2009 Dec, 132(Pt 12)
A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis.

[Abstract]The effect of interferon-beta in multiple sclerosis is modest and many patients do not respond to treatment. To date, no single biomarker reliably correlates with responsiveness to interferon-beta in multiple sclerosis. In the present study, genome-wide expression profiling was performed in peripheral blood mononuclear cells from 47 multiple sclerosis patients treated with interferon-beta for a minimum of 2 years and classified as responders and non-responders based on clinical criteria. A validation cohort of 30 multiple sclerosis patients was included in the study to replicate gene-expression findings. Before treatment, interferon-beta responders and non-responders were characterized by differential expression of type I interferon-induced genes with overexpression of the type interferon-induced genes in non-responders. Upon treatment the expression of these genes remained unaltered in non-responders, but was strongly upregulated in responders. Functional experiments showed a selective increase in phosphorylated STAT1 levels and interferon receptor 1 expression in monocytes of non-responders at baseline. When dissecting this type I interferon signature further, interferon-beta non-responders were characterized by increased monocyte type I interferon secretion upon innate immune stimuli via toll-like receptor 4, by increased endogenous production of type I interferon, and by an elevated activation status of myeloid dendritic cells. These findings indicate that perturbations of the type I interferon signalling pathway in monocytes are related to lack of response to interferon-beta, and type I interferon-regulated genes may be used as response markers in interferon-beta treatment.

88: Journal of neuroimmunology, 2009 Oct 30, 215(1-2)
Expression of T(H)1 and T(H)17 cytokines and transcription factors in multiple sclerosis patients: Does baseline T-Bet mRNA predict the response to interferon-beta treatment?

[Abstract]We studied the effect of one-year interferon (IFN)-beta treatment on the in vivo mRNA expression of IFN-gamma, interleukin (IL)-17, T-bet and RoR-gammat, on peripheral blood mononuclear cells (PBMC) from 36 multiple sclerosis (MS) patients. In the total MS group, IFN-beta induced decrease in mRNA levels of IFN-gamma and T-bet (p<0.0001), while the levels of IL-17 and RoR-gammat remained similar. In both responders and non-responders, IFN-beta induced significant decrease of IFN-gamma (p<0.0001 and p=0.011, respectively), while decrease in T-bet was detected only in responders (p<0.0001). Higher pre-treatment T-bet allowed prediction of the clinical response in the first year (beta=0.601, p=0.036). Our preliminary findings suggest that T-bet expression might be a potential prognostic marker of treatment response to IFN-beta in MS.

89: Journal of neurology, neurosurgery, and psychiatry, 2009 Dec, 80(12)
New acute and chronic black holes in patients with multiple sclerosis randomised to interferon beta-1b or glatiramer acetate.

[Abstract]BACKGROUND: Hypointense lesions on T1 weighted MRI, referred to as black holes (BH), are a marker of demyelination/axonal loss in multiple sclerosis (MS). There is some evidence that glatiramer acetate (GA) may decrease the conversion of new brain lesions to BH. METHODS: Monthly 3-Tesla brain MRI scans were used for up to 2 years to study the development and evolution of new BH in 75 patients with MS randomised to GA or Interferon beta-1b (IFNbeta1b) in the BECOME study. Findings: Of 1224 newly enhancing lesions (NEL) appearing at baseline through 24 months in 61 patients, 767 (62.7%) showed an acute BH (ABH). The majority of ABH were transient and of similar duration by treatment group. Of 571 ABH in which MRI follow-up scans were available for >or=1 year, 103 (18.8%) were still visible >or=12 months after onset and were considered chronic BH (CBH). Only 12.1% of the 849 NEL with MRI follow-up >or=1 year converted to CBH, 9.8% with IFNbeta1b and 15.2% with GA (p = 0.02). The conversion from ABH to CBH was also lower with IFNbeta1b (15.2%) than with GA (21.4%), of borderline significance (p = 0.06). The majority of patients who developed NEL did not develop CBH; however, about a quarter had conversion rates from ABH to CBH greater than 20%. Interpretation: Only a minority of new brain lesions in patients with MS treated with GA or IFNbeta1b convert to CBH.

90: Archives of neurology, 2009 Oct, 66(10)
Enhancement of chemokine expression by interferon beta therapy in patients with multiple sclerosis.

[Abstract]BACKGROUND: Interferon beta has been approved for the treatment of multiple sclerosis (MS). It is believed that immunomodulatory rather than antiviral activity of interferon beta is responsible for disease amelioration. The impact of interferon beta on the chemoattraction of immune cells has not been fully addressed. OBJECTIVE: To address the influence of interferon beta on the expression of chemokines and their receptors in a standardized setting. DESIGN: The expression of 14 chemokines and 14 chemokine receptor genes was determined by quantitative real-time polymerase chain reaction from fresh blood samples. SETTING: Outpatient units in Germany. Patients Untreated and interferon beta-treated patients with MS who tested positive and negative for neutralizing antibodies (NABs) were recruited from August 24, 2006, through December 15, 2006, for the initial study and from March 12, 2007, through April 2, 2007, for the validation study. MAIN OUTCOME MEASURES: Gene expression and serum chemokine protein levels. RESULTS: CCL1, CCL2, CCL7, CXCL10, CXCL11, and CCR1 gene expression was strongly upregulated in interferon beta-treated, NAB-negative MS patients. In contrast, gene expression in interferon beta-treated, NAB-positive MS patients did not differ from untreated control donor individuals. Antibody titers inversely correlated with chemokine and chemokine receptor gene expression. Accordingly, serum chemokine protein levels of interferon beta-treated, NAB-negative MS patients were significantly higher than in untreated or interferon beta-treated, NAB-positive MS patients. CONCLUSIONS: We demonstrate that interferon beta strongly upregulates a set of chemokines and CCR1 in peripheral immune cells. The peripheral upregulation of these chemokines may reduce the chemoattraction of immune cells to the central nervous system and thus add to the therapeutic effects of interferon beta.

91: Biochemical and biophysical research communications, 2009 Oct 16, 388(2)
The effect of interferon-beta on mouse neural progenitor cell survival and differentiation.

[Abstract]Interferon-beta (IFN-beta) is a mainstay therapy for relapse-remitting multiple sclerosis (MS). However, the direct effects of IFN-beta on the central nervous system (CNS) are not well understood. To determine whether IFN-beta has direct neuroprotective effects on CNS cells, we treated adult mouse neural progenitor cells (NPCs) in vitro with IFN-beta and examined the effects on proliferation, apoptosis, and differentiation. We found that mouse NPCs express high levels of IFNalpha/beta receptor (IFNAR). In response to IFN-beta treatment, no effect was observed on differentiation or proliferation. However, IFN-beta treated mouse NPCs demonstrated decreased apoptosis upon growth factor withdrawal. Pathway-specific polymerase chain reaction (PCR) arrays demonstrated that IFN-beta treatment upregulated the STAT 1 and 2 signaling pathway, as well as GFRA2, NOD1, Caspases 1 and 12, and TNFSF10. These results suggest that IFN-beta can directly affect NPC survival, possibly playing a neuroprotective role in the CNS by modulating neurotrophic factors.

92: Journal of cancer research and clinical oncology, 2010 Jan, 136(1)
Nasopharyngeal carcinoma in adults: treatment results after long-term follow-up with special reference to adjuvant interferon-beta in undifferentiated carcinomas.

[Abstract]PURPOSE: Nasopharyngeal carcinomas (NPC) are radiosensitive, and radiotherapy is the standard curative treatment. Furthermore, it has been shown that combined radiochemotherapy improves prognosis in locally advanced stages. Further encouraging results have been obtained with adjuvant interferon-beta after primary radio(chemo)therapy in childhood undifferentiated NPC. Aim of the present study was to evaluate the treatment results after long-term follow-up after radio(chemo)therapy for adult NPC with special reference to patients with undifferentiated carcinomas treated with adjuvant interferon-beta. PATIENTS AND METHODS: From 02/1992 to 07/2008, 26 adult patients with NPC without distant metastases were treated (17 squamous cell carcinomas, 9 undifferentiated carcinomas). The treatment concepts changed over the years: 13 patients were treated with radiotherapy alone, 13 patients received combined radiochemotherapy. Additionally, six patients with undifferentiated carcinomas were treated with adjuvant interferon-beta after radiochemotherapy for 6 months. RESULTS: After a median follow-up of 96 months, 17 patients remain alive. Collectively, our 5-year overall-survival and loco-regional control rates were 74% (radiochemotherapy 81%, radiotherapy alone 68.5%) and 87% (radiochemotherapy 100%, radiotherapy alone 72.7%), respectively. All treatment regimens used were feasible; especially, adjuvant interferon-beta was applied as provided without high grade toxicity. All patients with undifferentiated carcinomas treated with adjuvant interferon-beta stayed alive until the end of the follow-up. CONCLUSION: In summary, our data affirm that NPC in adults are curable by primary radio(chemo)therapy. Furthermore, our data indicate that adjuvant interferon-beta application in undifferentiated NPC in adults is feasible and shows promising results. Further prospective clinical trials are needed to finally establish adjuvant interferon beta in curative treatment of adult NPC.

93: Clinical immunology (Orlando, Fla.), 2009 Oct, 133(1)
Interferon-beta treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1.

[Abstract]Interferon-beta is a current treatment for multiple sclerosis (MS). Interferon-beta is thought to exert its therapeutic effects on MS by down-modulating the immune response by multiple potential pathways. Here, we document that treatment of MS patients with interferon beta-1a (Rebif) results in a significant increase in the levels and function of the protein tyrosine phosphatase SHP-1 in PBMCs. SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and CNS demyelination as evidenced in mice deficient in SHP-1. In order to examine the functional significance of SHP-1 induction in MS PBMCs, we analyzed the activity of proinflammatory signaling molecules STAT1, STAT6, and NF-kappaB, which are known SHP-1 targets. Interferon-beta treatment in vivo resulted in decreased NF-kappaB and STAT6 activation and increased STAT1 activation. Further analysis in vitro showed that cultured PBMCs of MS patients and normal subjects had a significant SHP-1 induction following interferon-beta treatment that correlated with decreased NF-kappaB and STAT6 activation. Most importantly, experimental depletion of SHP-1 in cultured PBMCs abolished the anti-inflammatory effects of interferon-beta treatment, indicating that SHP-1 is a predominant mediator of interferon-beta activity. In conclusion, interferon-beta treatment upregulates SHP-1 expression resulting in decreased transcription factor activation and inflammatory gene expression important in MS pathogenesis.

94: European journal of neurology : the official journal of the European Federation of Neurological Societies, 2009 Dec, 16(12)
Identification of new sensitive biomarkers for the in vivo response to interferon-beta treatment in multiple sclerosis using DNA-array evaluation.

[Abstract]Objective: Neutralizing antibodies (NAbs) occur in a proportion of multiple sclerosis (MS) patients treated with interferon (IFN)-beta. NAbs impair the effect of treatment. The biological effect of IFN-beta can be measured as the induction of the myxovirus resistance protein A (MxA) molecule. However, other markers could be more sensitive for evaluating the response to IFN-beta. We used DNA array analysis to identify genes that are strongly induced in blood cells by IFN-beta, and measured their expression in MS patients with different NAb levels. Methods: Gene expression was studied on DNA arrays in untreated patients, in NAb negative patients, and in MS patients with varying NAb levels 9-12 h and 36-48 h after IFN-beta administration. The expression of selected genes was measured by real-time PCR. NAb levels were assessed by a cytopathic effect assay. Results: Several hundred genes were induced 9-12 h after an injection of IFN-beta. The molecules CXCL10, CCL2 and IFI27 were among the most strongly induced. Gene induction was generally much less pronounced after 36-48 h, but IFI27 remained strongly induced. The strong induction of these molecules and MxA was confirmed by real-time PCR. Induction of MxA, CCL2, CXCL10 and IFI27 was reduced in patients with low NAb levels and lost in patients with intermediate/high NAb levels. Conclusion: We identify IFI27, CCL2 and CXCL10 as sensitive biomarkers for the response to IFN-beta. The expression of these markers adequately reflects bioactivity of IFN-ss as documented by the decreased induction in low NAb-positive patients and the lost induction in patients with moderate/high NAb levels.

95: Clinical and experimental dermatology, 2009 Oct, 34(7)
Perilesional treatment of metastatic melanoma with interferon-beta.

[Abstract]Previous trials with various treatments have not shown satisfactory therapeutic results for cutaneous metastasis of malignant melanoma (MM). We report three patients who were treated with peritumoral injection of interferon (IFN)-beta for multiple skin metastases of MM. The metastatic tumours were infiltrated by significant numbers of CD8+ TIA+ cytotoxic lymphocytes, and the numbers of CD4+ cells and human leucocyte antigen-DR+ cells increased after IFN-beta injection. These results suggest that the peritumoral administration of IFN-beta enhanced the antitumour immune response against the MM, suggesting that it is a promising supportive treatment for skin metastasis of MM.

96: Transplantation proceedings, 2009 Jan-Feb, 41(1)
Efficacy of interferon Beta combined with cyclosporine induction and intensified therapy for retreatment of chronic hepatitis C.

[Abstract]OBJECTIVE: Hepatitis C virus (HCV) infection is a major burden after liver transplantation. There is no effective treatment for these patients, therefore management is challenging. Cyclophilins are essential host factors for HCV replication. We have reported herein the efficacy of divided administration of interferon (IFN) beta plus cyclosporine for chronic hepatitis C patients who failed pegylated (Peg)-IFN or IFN combined ribavirin treatment. PATIENTS AND METHODS: We prospectively enrolled 59 patients (median age, 63 years) with genotype 1b who failed to respond to the combinations of IFN plus ribavirin or Peg-IFN plus ribavirin. Our treatment involved induction, intensified, and maintenance therapies. The induction therapy prescribed intravenous 1 MU IFN beta every 4 hours for the first 3 days, 1.5 MU IFN beta every 6 hours for the next 4 days, and then 2 MU IFN beta every 8 hours for 3 weeks. The intensified therapy was the induction therapy shortened to 2 weeks. The maintenance therapy involved Peg-IFN alpha 2b and ribavirin. Cyclosporine was given 4 times daily during the induction and intensified therapies. Ribavirin was given twice daily during the maintenance phase. RESULTS: The end treatment and sustained virological response rates in the present study were 73% (43/59) and 59% (35/59), respectively. The relapse rate was 19% (8/43). Sixteen percent of patients (3/19) were nonresponders. All adverse effects were reversible. The treatment protocol was well tolerated. CONCLUSION: Our protocol should be effective for patients who have failed previous combination therapies.

97: Neuroimmunomodulation, 2009 Feb 24, 16(3)
Interferon beta-1a Induces Tumor Necrosis Factor Receptor 1 but Decreases Tumor Necrosis Factor Receptor 2 Leukocyte mRNA Levels in Relapsing-Remitting Multiple Sclerosis.

[Abstract]Objective: Members of the tumor necrosis factor (TNF) receptor superfamily play a major role in the pathogenesis of multiple sclerosis. To elucidate the role of TNF receptors, in 53 relapsing-remitting multiple sclerosis patients, we measured the TNF receptor 1 and receptor 2 (TNF-R1 and TNF-R2) mRNA levels in peripheral blood leukocytes in natural history (n = 27) and during administration of interferon (IFN) beta-1a (n = 26). Methods: Every 3 months for the duration of 1 year peripheral blood leukocytes were investigated by quantitative reverse transcription polymerase chain reaction. Every 6 months, MRI scans of the brain were analyzed semiquantitatively. Results: At baseline, clinical expanded disability status scale score and TNF-R1 mRNA level were correlated. In the therapy group, the difference between T2 lesion load at baseline and after 12 months correlated negatively with the difference between TNF-R1 mRNA level at baseline and after 12 months. Subcutaneously applied IFN beta increased the amount of TNF-R1 mRNA, but partly decreased the amount of TNF-R2 mRNA in clinically and subclinically defined responders to therapy after 1 year compared to baseline. Conclusion: This result might support the notion that due to different signal transduction properties of both receptors in the natural course of multiple sclerosis, TNF-alpha signaling in leukocytes via TNF-R1 might be beneficial, but detrimental via proinflammatory TNF-R2: part of the therapeutic efficacy of current first-line standard therapy with IFN might be due to the modulation of signal transduction pathways.

98: Journal of neurology, 2009 Feb 25, 16(3)
Interferon beta, birth weight and pregnancy in multiple sclerosis.

[Abstract]Objective: Members of the tumor necrosis factor (TNF) receptor superfamily play a major role in the pathogenesis of multiple sclerosis. To elucidate the role of TNF receptors, in 53 relapsing-remitting multiple sclerosis patients, we measured the TNF receptor 1 and receptor 2 (TNF-R1 and TNF-R2) mRNA levels in peripheral blood leukocytes in natural history (n = 27) and during administration of interferon (IFN) beta-1a (n = 26). Methods: Every 3 months for the duration of 1 year peripheral blood leukocytes were investigated by quantitative reverse transcription polymerase chain reaction. Every 6 months, MRI scans of the brain were analyzed semiquantitatively. Results: At baseline, clinical expanded disability status scale score and TNF-R1 mRNA level were correlated. In the therapy group, the difference between T2 lesion load at baseline and after 12 months correlated negatively with the difference between TNF-R1 mRNA level at baseline and after 12 months. Subcutaneously applied IFN beta increased the amount of TNF-R1 mRNA, but partly decreased the amount of TNF-R2 mRNA in clinically and subclinically defined responders to therapy after 1 year compared to baseline. Conclusion: This result might support the notion that due to different signal transduction properties of both receptors in the natural course of multiple sclerosis, TNF-alpha signaling in leukocytes via TNF-R1 might be beneficial, but detrimental via proinflammatory TNF-R2: part of the therapeutic efficacy of current first-line standard therapy with IFN might be due to the modulation of signal transduction pathways.

99: Expert opinion on pharmacotherapy, 2009 Feb, 10(2)
High-dose, high-frequency recombinant interferon beta-1a in the treatment of multiple sclerosis.

[Abstract]BACKGROUND: There is at present no cure for multiple sclerosis (MS), and existing therapies are designed primarily to prevent lesion formation, decrease the rate and severity of relapses and delay the resulting disability by reducing levels of inflammation. OBJECTIVE: The aim of this review was to assess the treatment of relapsing MS with particular focus on subcutaneous (s.c.) interferon (IFN) beta-1a. METHOD: The literature on IFN beta-1a therapy of MS was reviewed based on a PubMed search (English-language publications from 1990) including its pharmacodynamics and pharmacokinetics, clinical efficacy in relapsing MS as shown in placebo-controlled studies and in comparative trials, efficacy in secondary progressive MS, safety and tolerability, and the impact of neutralizing antibodies. CONCLUSION: The literature suggests that high-dose, high-frequency s.c. IFN beta-1a offers an effective option for treating patients with relapsing MS, with proven long-term safety and tolerability, and has a favourable benefit-to-risk ratio compared with other forms of IFN beta.

100: European journal of neurology : the official journal of the European Federation of Neurological Societies, 2009 Feb 13, 10(2)
Vitiligo and multiple sclerosis in a patient treated with interferon beta-1a: a case report.

[Abstract]BACKGROUND: There is at present no cure for multiple sclerosis (MS), and existing therapies are designed primarily to prevent lesion formation, decrease the rate and severity of relapses and delay the resulting disability by reducing levels of inflammation. OBJECTIVE: The aim of this review was to assess the treatment of relapsing MS with particular focus on subcutaneous (s.c.) interferon (IFN) beta-1a. METHOD: The literature on IFN beta-1a therapy of MS was reviewed based on a PubMed search (English-language publications from 1990) including its pharmacodynamics and pharmacokinetics, clinical efficacy in relapsing MS as shown in placebo-controlled studies and in comparative trials, efficacy in secondary progressive MS, safety and tolerability, and the impact of neutralizing antibodies. CONCLUSION: The literature suggests that high-dose, high-frequency s.c. IFN beta-1a offers an effective option for treating patients with relapsing MS, with proven long-term safety and tolerability, and has a favourable benefit-to-risk ratio compared with other forms of IFN beta.

101: Journal of virology, 2009 Feb 4, 10(2)
The human respiratory syncytial virus nonstructural NS2 protein antagonizes the activation of interferon-{beta} transcription by interacting with RIG-I.

[Abstract]A wide variety of RNA viruses have been shown to produce proteins that inhibit interferon (IFN) production and signaling. For human respiratory syncytial virus (RSV), the nonstructural NS1 and NS2 proteins have been shown to block IFN signaling by causing the proteasomal degradation of STAT2. In addition, recombinant RSVs lacking either NS1 or NS2 induce more IFN production than wild-type RSV in infected cells. However, the mechanisms by which the NS proteins perform this function are unknown. In this study, we focused on defining the mechanism by which NS2 inhibits the induction of IFN transcription. We find that NS2 is required for early inhibition of IFN transcription since infection of cells with NS2-deletion RSV resulted in a higher level of IRF3 activation at early time points post-infection compared with wt or NS1-deletion RSV infection. In addition, NS2 expression inhibits IFN transcription induced by both the RIG-I and TLR3 pathways. Furthermore, we show that NS2 inhibits RIG-I-mediated IFN promoter activation by binding to the N-terminal CARD domains of RIG-I and inhibiting its interaction with the downstream component MAVS (IPS-1, VISA, Cardif). Thus, the RSV NS2 protein is a multifunctional IFN antagonist that target specific components of both the IFN induction and IFN signaling pathways.


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