Fingolimod (FTY720) ameliorates experimental autoimmune encephalomyelitis (EAE): I. Oral administration of FTY720 effectively inhibits relapse of EAE

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a CD4 T cell-mediated disease model for multiple sclerosis (MS). When SJL/J mice are immunized with myelin proteolipid protein (PLP), EAE symptoms were developed within 2 weeks, remitted thereafter, and then relapsed at about 3 weeks after immunization, indicating that EAE induced by PLP in SJL/J mice shares a certain characteristic with relapsing remitting MS. In this study, we evaluated the preventing effect of fingolimod (FTY720), a sphingosine 1-phosphate receptor modulator, on relapse of EAE induced by PLP in SJL/J mice. When FTY720 at oral does of 0.1 and 0.3 mg/kg was administered daily after establishment of EAE, relapse of EAE was markedly inhibited during administration period. The relapse of EAE was significantly inhibited by subcutaneous administration of recombinant mouse interferon-β (rm-IFN-β) at 10000 IU every other day at early period; however EAE was relapsed in the half number of mice in latter period. These results indicate that FTY720 shows a more marked preventing effect on relapse of EAE compared with rm-IFN-β. By immunohistochemical staining, it is revealed that the area of demyelination and the infiltration of CD4 T cells are significantly reduced in the spinal cords of EAE mice by FTY720. Interestingly, FTY720 markedly decreased infiltration of PLP-specific, interleukin 17-expressing CD4 T cells (Th17 cells) into the spinal cords. Consequently, the preventing effect of FTY720 on relapse of EAE is likely due to reduction of infiltration of encephalitogenic CD4 T cells into the central nervous system.