Long-term favorable response to interferon beta-1b is linked to cytokine deviation toward the Th2 and Tc2 sides in Japanese patients with multiple sclerosis

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Abstract

To address the immune mechanism of the long-term beneficial effects of interferon beta (IFN-β), we measured the intracellular cytokine production patterns of IFN-γ, IL-4 and IL-13 in peripheral blood CD4+ and CD8+ T cells, which previously displayed alterations during the early course of IFN-β treatment, in 15 Japanese patients after long-term IFN-β administration. The patients were treated with IFN-β-1b 8 × 106 units given subcutaneously every other day for a mean period of 34.5 ± 5.5 months (range: 26–43 months). During the follow-up period, 6 patients experienced 33 relapses, while the other 9 were relapse-free. The results revealed the following cytokine alterations: (1) type 2 cytokine, such as IL-4 and IL-13, were significantly increased in producing cell percentages in both CD4+ (p = 0.0356 and p = 0.0007, respectively) and CD8+ (p = 0.0231 and p = 0.0170, respectively) T cells while IFN-γ, a representative type 1 cytokine, was significantly decreased in the absolute producing cell numbers (p = 0.0125 in CD4+ T cells and p = 0.0022 in CD8+ T cells) even after approximately 3 years of IFN-β administration; (2) the intracellular IFN-γ / IL-4 ratio tended to decrease in both CD4+ and CD8+ T cells (p = 0.0535 and p = 0.0783, respectively), reflecting a strong downmodulation of type 1 cytokine producing cells; and importantly (3) alterations such as the decreased intracellular IFN-γ / IL-4 ratio in CD4+ T cells and increased percentage of CD8+ IL-13+ T cells compared with the pretreatment levels were only statistically significant in MS patients without relapse during IFN-β therapy (p = 0.0152 and p = 0.0078, respectively). Therefore, we consider that cytokine deviation toward the Th2 and Tc2 sides is linked to a long-term favorable response to IFN-β, while a higher intracellular IFN-γ / IL-4 ratio is associated with treatment failure.

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is generally considered to be mediated by myelin-autoreactive T cells. Interferon beta (IFN-β) reduces the frequency and severity of clinical relapses in relapsing–remitting MS, and the basis of these beneficial effects has been extensively studied both in vivo and in vitro.

The effects of IFN-β on the cytokine production pattern is especially important, since increasing evidence suggests that MS is largely caused by CD4+ T helper 1 (Th1) cells that produce interferon gamma (IFN-γ) but not interleukin (IL)-4 [1]. Moreover, important roles of CD8+ T cells have also been suggested by the selective enrichment of memory CD8+ T cells in the cerebrospinal fluid (CSF) of MS patients [2] together with diffuse infiltration of clonally expanded CD8+ T cells into the brain parenchyma [3], [4]. However, most previous cytokine studies on the effects of IFN-β have been performed within 1 year after initiation of the therapy [5], [6], [7], [8], [9], [10], although the beneficial effects of IFN-β persist for several years [11]. Thus, although the long-term beneficial effects of IFN-β are well established, the basis of these effects in vivo remains to be fully elucidated. We recently performed sequential measurements of multiple cytokine production patterns in both CD4+ and CD8+ T cells from the pretreatment period up to 48 months after initiation of the therapy, and found early increases in Th2 cytokines, such as IL-4 and IL-13, followed by late decreases in Th1 cytokines, such as IFN-γ, in both conventional MS (C-MS) and opticospinal MS (OS-MS) [12]. In the present study, we focused on the cytokines that displayed significant alterations in our previous study and evaluated the long-term effects of IFN-β on the cytokine production patterns in CD4+ and CD8+ T cells in the peripheral blood of MS patients several years after initiation of the drug treatment.

Section snippets

Patients

Fifteen Japanese patients (8 women and 7 men; mean age ± SD: 42.13 ± 12.44 years) with relapsing–remitting MS, diagnosed according to the revised diagnostic criteria for MS [13] and treated with IFN-β-1b (Betaferon®; Shering) 8 × 106 units given subcutaneously every other day for at least 2 years (mean period ± SD: 34.5 ± 5.5 months; range: 26–43 months), were included in this study. At the time of their enrollment, none of the patients were experiencing an acute attack or had been under

Clinical responses to IFN-β therapy

During the 2–3 year observation period, 6 patients suffered 33 relapses: 1 patient experienced 10 relapses, 1 experienced 8 relapses, 1 experienced 5 relapses, 2 experienced 4 relapses and 1 experienced 2 relapses. The remaining 9 patients did not have any relapses during the follow-up period. During this period, 5 of 13 (38%) C-MS patients and 1 of 2 (50%) OS-MS patients relapsed. The gender ratio, age at baseline, EDSS scores and annual relapse rate before initiation of the IFN-β-1b therapy

Discussion

This study revealed the following long-term effects of IFN-β on the intracellular cytokine production patterns of peripheral blood CD4+ and CD8+ T cells in MS patients: (1) type 2 cytokines, such as IL-4 and IL-13, were significantly increased in producing cell percentages in both CD4+ and CD8+ T cells while IFN-γ, a representative type 1 cytokine, was significantly decreased in the absolute producing cell numbers in both CD4+ and CD8+ T cells, even after approximately 3 years of IFN-β

Acknowledgements

We thank K. Matsuzaki and T. Tanaka for their helpful assistance. This study was supported in part by a Neuroimmunological Disease Research Committee grant and a Research on Brain Science grant from the Ministry of Health, Labor and Welfare of Japan, and Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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These authors contributed equally to this work.

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