FTY720,Sphingosine 1-Phosphate Receptor Modulator,Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibition of T Cell Infiltration

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.