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
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.