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

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.