Time-dependent cytokine deviation toward the Th2 side in Japanese multiple sclerosis patients with interferon beta-1b

Abstract 

To address the immune mechanism sustaining interferon beta (IFNβ) efficacy in multiple sclerosis (MS), we longitudinally analyzed expressions of IFN-γ, IL-4, IL-5 and IL-13 in CD4⁺ T cells and CD8⁺ T cells in 22 Japanese MS patients (16 patients with conventional MS and 6 with opticospinal MS) undergoing IFNβ using flow cytometry. During the 48-week observation period, five opticospinal MS patients (83%) relapsed compared to only four conventional MS patients (25%); the frequency of relapsed patients was significantly higher in the former (p=0.046). The effects of IFNβ on individual cytokines were time-dependent and altered cytokine productions were particularly evident in CD4⁺ rather than CD8⁺ T cells. A decreased intracellular IFN-γ/IL-4 ratio in CD4⁺ T cells was thus evident soon after the initiation of therapy, and persisted for the entire 1 year follow-up period, regardless of whether or not the patient relapsed (p<0.01). IFNβ treatment resulted in a rapid increase in the percentage of IFN-γ⁻ IL-4⁺ and IL-13⁺ CD4⁺ T cells 1 week after the initiation of therapy and high values were sustained for 6 months but declined to the baseline over 1 year. Later, the percentage of IFN-γ⁺ IL-4⁻ CD4⁺ T cells decreased significantly from weeks 24 through 48 of therapy (p<0.01). When comparisons with the pretreatment values were made for each subtype of MS, a significant reduction of IFN-γ⁺ IL-4⁻ CD4⁺ T cell percentages was shown in conventional MS (p<0.0001), but not in opticospinal MS. Moreover, when such a comparison was made by the presence or absence of relapse during therapy, a significant reduction of IFN-γ⁺ IL-4⁻ CD4⁺ T cell percentages was observed in MS patients without relapse (p<0.01). Thus, a reduction of IFN-γ⁺ IL–4⁻ CD4⁺ T cell percentages in the late phase of therapy is considered important for reducing relapse in conventional MS. When the expression patterns of IFN-γ, IL-4, IL-5 and IL-13 in CD4⁺ T cells and CD8⁺ T cells were compared between patients with and without relapse during therapy, the only significant difference was an increase in the IL-13⁺ CD4⁺ T cell percentages in patients with relapse compared to those without (p<0.05). The results indicate that in CD4⁺ T cells IL-4 was preferentially up-regulated in the early course and IFN-γ was down-regulated in the late phase of IFNβ therapy. The net effect of IFNβ on the immune balance was entirely toward type 2 immune deviation, possibly contributing to its beneficial effects on MS.

Keywords:  Multiple sclerosis, Interferon beta, IFNγ, IL-4, IL-13, Th1, Th2, Opticospinal MS