FTY720,a sphingosine 1-phosphate receptor modulator,induces a marked decrease in the number of peripheralblood lymphocytes and exerts immunomodulating activity in various experimental allograft and autoimmunedisease models.In this study,we evaluated the effect of FTY720 and its active metabolite,(S)-enantiomer ofFTY720-phosphate [(S)-FTY720-P] on experimental autoimmune encephalomyelitis (EAE) in rats and mice.Prophylactic administration of FTY720 at 0.1 to 1mg/kg almost completely prevented the development of EAE,and therapeutic treatment with FTY720 significantly inhibited the progression of EAE and EAE-associatedhistological change in the spinal cords of LEW rats induced by immunization with myelin basic protein.Consistentwith rat EAE,the development of proteolipid protein-induced EAE in SJL/J mice was almost completely preventedand infiltration of CD4~+ T cells into spinal cord was decreased by prophylactic treatment with FTY720 and(S)-FTY720-P.When FTY720 or (S)-FTY720-P was given after establishment of EAE in SJL/J mice,the relapse ofEAE was markedly inhibited as compared with interferon-β,and the area of demyelination and the infiltration ofCD4~+ T cells were decreased in spinal cords of EAE mice.Similar therapeutic effect by FTY720 was obtained inmyelin oligodendrocyte glycoprotein-induced EAE in C57BL/6 mice.These results indicate that FTY720 exhibitsnot only a prophylactic but also a therapeutic effect on EAE in rats and mice,and that the effect of FTY720 onEAE appears to be due to a reduction of the infiltration of myelin antigen-specific CD4~+ T cells into theinflammation site.Cellular & Molecular Immunology.2005;2(6):439-448. FTY720, a sphingosine 1-phosphate receptor modulator, induces a marked decrease in the number of peripheral blood lymphocytes and exerts immunomodulating activity in various experimental allografts and autoimmune disease models. In this study, we evaluated the effect of FTY720 and its active metabolite, (S) -enantiomer of FTY720-phosphate [(S) -FTY720-P] on experimental autoimmune encephalomyelitis (EAE) in rats and mice. Prophylactic administration of FTY720 at 0.1 to 1 mg / kg almost completely prevented the development of EAE, and therapeutic treatment with FTY720 inhibited the progression of EAE and EAE-associated histological change in the spinal cord of LEW rats induced by immunization with myelin basic protein. Canonical with rat EAE, the development of proteolipid protein-induced EAE in SJL / J mice was almost completely prevented and infiltration of CD4 ~ + T cells into spinal cord was reduced by prophylactic treatment with FTY720 and (S) -FTY720-P.When FTY720 or (S) -FTY720-P was given after establishment of EAE in SJL / J mice, the relapse of EAE was markedly inhibited as compared with interferon-beta, and the area of ​​demyelination and the infiltration of CD4 + T cells were decreased in spinal cords of EAE mice. Similar therapeutic effect by FTY720 was obtained in myelin oligodendrocyte glycoprotein-induced EAE in C57BL / 6 mice.These results indicate that FTY720 exhibits only a prophylactic but also a therapeutic effect on EAE in rats and mice, and that the effect of FTY720 onEAE appears to be due to a reduction of the infiltration of myelin antigen-specific CD4 ~ + T cells into the inflamation site. Cellular & Molecular Immunology. 2005; 2 (6): 439-448.