Cytokine changes during interferon-beta therapy in multiple sclerosis: Correlations with interferon dose and MRI response

Graber, Jerome; Ford, David A.; Zhan, Min; Francis, Gordon; Panitch, Hillel S.; Dhib‐Jalbut, Suhayl

doi:10.1016/j.jneuroim.2007.01.011

Cited by 66 publications

(27 citation statements)

References 45 publications

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“…More notably, consistent with an inhibitory role of Sema4A in IL-10 production (35), we found that patients with high serum Sema4A levels had low serum IL-10 levels. Because IL-10 has been linked to the beneficial effects of IFN-b treatment (24,48), it is plausible that high Sema4A levels result in decreased IL-10 levels, leading to the unresponsiveness to IFN-b therapy.…”

Section: Discussionmentioning

confidence: 99%

Elevation of Sema4A Implicates Th Cell Skewing and the Efficacy of IFN-β Therapy in Multiple Sclerosis

Nakatsuji

Okuno

Moriya

et al. 2012

The Journal of Immunology

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Multiple sclerosis (MS) is a demyelinating autoimmune disease of the CNS and a leading cause of lasting neurologic disabilities in young adults. Although the precise mechanism remains incompletely understood, Ag presentation and subsequent myelin-reactive CD4+ T cell activation/differentiation are essential for the pathogenesis of MS. Although semaphorins were initially identified as axon guidance cues during neural development, several semaphorins are crucially involved in various phases of immune responses. Sema4A is one of the membrane-type class IV semaphorins, which we originally identified from the cDNA library of dendritic cell (DC). Sema4A plays critical roles in T cell activation and Th1 differentiation during the course of experimental autoimmune encephalomyelitis, an animal model of MS; however, its pathological involvement in human MS has not been determined. In this study, we report that Sema4A is increased in the sera of patients with MS. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner. DC-derived Sema4A is not only critical for Th1 but also for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-β treatment. Taken together, our results suggest that Sema4A is involved in the pathogenesis of MS by promoting Th17 skewing.

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Section: Discussionmentioning

confidence: 99%

Elevation of Sema4A Implicates Th Cell Skewing and the Efficacy of IFN-β Therapy in Multiple Sclerosis

Nakatsuji

Okuno

Moriya

et al. 2012

The Journal of Immunology

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“…Since IFNβ comprises a first-line defense against acute virus infections, the antiviral effects of various therapeutic IFNβ variants may represent a partial explanation for their favorable effects in MS. Another rationale for clinical trials with IFNβs is based on the assumption that cytokines from both immune and non-immune cells play a major role in MS pathophysiology and that IFNβ downregulates proinflammatory Th1 cytokines and upregulates antiinflammatory Th2 cytokines [36,37,38]. However, changes in the profile of Th1/Th2 cytokines during long-term monotherapy with IFNβ-1a or IFNβ-1b have not been investigated in patients with RRMS.…”

Section: Introductionmentioning

confidence: 99%

Effects of Interferon β-1a and Interferon β-1b Monotherapies on Selected Serum Cytokines and Nitrite Levels in Patients with Relapsing-Remitting Multiple Sclerosis: A 3-Year Longitudinal Study

Stępień

Chalimoniuk²,

Lubina-Dąbrowska

et al. 2013

Neuroimmunomodulation

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Objective: Interferon (IFN)β treatment is a mainstay of relapsing-remitting multiple sclerosis (RRMS) immunotherapy. Its efficacy is supposedly a consequence of impaired trafficking of inflammatory cells into the central nervous system and modification of the proinflammatory/antiinflammatory cytokine balance. However, the effects of long-term monotherapy using various IFNβ preparations on cytokine profiles and the relevance of these effects for the therapy outcome have not yet been elucidated. Methods: Changes were compared in serum levels of TNFα, IFNγ, interleukin (IL)-6, IL-10 and nitrite between RRMS patients given 3-year treatment with intramuscular IFNβ-1a (30 μg once a week) or subcutaneous IFNβ-1b (250 μg every other day). Only the data from patients who completed the 3-year study (n = 20 and n = 18, respectively) were analyzed. Results: Three-year IFNβ-1a or IFNβ-1b monotherapy reduced serum nitrite levels by 77 and 71%, respectively, lowered multiple sclerosis relapse annual rate by 70 and 71%, respectively, and significantly and similarly lowered Expanded Disability Status Scale scores in both study groups (by 0.9 on average). The two monotherapies showed little if any effect on cytokine levels and cytokine level ratios after the first year, but exerted diverging effects on these indices later on; the only exception was the IFNγ/IL-6 ratio that showed a monotonous rise in both study groups over the entire study period. Conclusion: During long-term IFNβ monotherapy, the levels of the studied cytokines show no relevance to the course of RRMS and neurological status of patients, whereas there seems to be a link between these clinical indices and the activity of nitric oxide-mediated pathways.

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“…In addition, many serum biomarkers are non-specific indicators of systemic inflammation and may also be altered during even minor infections [4]. Another obstacle to interpreting studies of biomarkers in response to therapy is differences in the formulations of IFN-β used in different studies, which have been shown to have different effects on biomarkers of disease [5][6][7]. Numerous biomarkers of disease activity have been explored encompassing cytokines, chemokines, immune cell subsets, costimulatory molecules, antibodies, vascular adhesion and permeability and neuronal and glial damage, among others (Tables 3-8).…”

Section: Introductionmentioning

confidence: 99%

Biomarkers of disease activity in multiple sclerosis

Graber

Dhib‐Jalbut²

2011

Journal of the Neurological Sciences

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Cytokine changes during interferon-beta therapy in multiple sclerosis: Correlations with interferon dose and MRI response

Cited by 66 publications

References 45 publications

Elevation of Sema4A Implicates Th Cell Skewing and the Efficacy of IFN-β Therapy in Multiple Sclerosis

Elevation of Sema4A Implicates Th Cell Skewing and the Efficacy of IFN-β Therapy in Multiple Sclerosis

Effects of Interferon β-1a and Interferon β-1b Monotherapies on Selected Serum Cytokines and Nitrite Levels in Patients with Relapsing-Remitting Multiple Sclerosis: A 3-Year Longitudinal Study

Biomarkers of disease activity in multiple sclerosis

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