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 allograft 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 significantly inhibited the progression of EAE and EAE-associated histological change in the spinal cords of LEW rats induced by immunization with
myelin basic protein. Consistent 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 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 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 not only a prophylactic but also a
therapeutic effect on EAE in rats and mice, and that the effect of
FTY720 on EAE appears to be due to a reduction of the infiltration of myelin
antigen-specific CD4(+) T cells into the
inflammation site.