Fingolimod (FTY720) ameliorates experimental autoimmune encephalomyelitis (EAE): II. FTY720 decreases infiltration of Th17 and Th1 cells into the central nervous system in EAE

Abstract

Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) receptor modulator, is highly effective in experimental autoimmune encephalomyelitis (EAE) and decreases circulating mature lymphocytes by inhibiting S1P-dependent lymphocyte egress from secondary lymphoid organs. Infiltration of encephalitogenic CD4 T cells plays a critical role in the development and progression of EAE in mice. In this study, we investigated the effects of FTY720 on infiltration of interleukin 17 (IL-17)-expressing helper T cells (Th17 cells) and interferon-γ-expressing type 1 helper T cells (Th1 cells) into the spinal cords in EAE mice induced by immunization with myelin oligodendrocyte glycoprotein (MOG). Prophylactic treatment with FTY720 at an oral dose of 0.3 mg/kg significantly inhibited the development of EAE and markedly reduced the frequency of Th17 and Th1 cells in the spinal cords of EAE mice. On the contrary, the frequency of Th17 and Th1 cells in draining inguinal lymph nodes was increased to approximately 2-fold by FTY720, suggesting sequestration of myelin antigen-specific Th cells into draining lymph nodes. Moreover, we found that Th17 and Th1 cells could migrate toward 10 nM S1P and that the pretreatment with 1 nM FTY720-phosphate, an active metabolite of FTY720, almost completely inhibited S1P-induced migration of these Th cells. On the other hand, FTY720-phosphate up to 100 nM showed no clear effect on generation of these Th cells or cytokine production by them. From these results, the ameliorating effects of FTY720 on EAE are likely due to reduction of infiltration of encephalitogenic Th17 and Th1 cells into the central nervous system.