title: FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration.
abstract: 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.
authors.affiliation: Research Laboratory III (Immunology), Pharmaceutical Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, Yokohama, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Kunio
authors.initials: K
authors.lastname: Sugahara
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shimano
authors.forename: Koji
authors.initials: K
authors.lastname: Teshima
authors.forename: Mamoru
authors.initials: M
authors.lastname: Koyama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukunari
authors.forename: Kenji
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D000068876:Fingolimod Hydrochloride; D006023:Glycoproteins / Q000494:pharmacology; D008297:Male; D051379:Mice; D004676:Myelin Basic Protein / Q000494:pharmacology; D018991:Myelin Proteolipid Protein / Q000494:pharmacology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*
chemical_list: D006023:Glycoproteins; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C445081:myelin oligodendrocyte glycoprotein (35-55); C435023:myelin proteolipid protein (139-151); D000068876:Fingolimod Hydrochloride; D013110:Sphingosine