Fingolimod (FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-β in mouse experimental autoimmune encephalomyelitis.
Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) receptor modulator, inhibits S1P-dependent lymphocyte egress from secondary lymphoid organs and is highly effective in experimental autoimmune encephalomyelitis (EAE) in mice. In this study, we directly compared the therapeutic effects of FTY720 and recombinant mouse interferon (rm-IFN)-β on relapse and progression of EAE in mice. When FTY720 at oral dose of 0.03 to 1 mg/kg was administered daily after establishment of EAE induced by myelin proteolipid protein (PLP) in SJL/J mice, relapse of EAE was significantly inhibited during administration period. Subcutaneous injection of rm-IFN-β (10,000 IU/mouse) also inhibited the relapse of EAE at early period; however EAE was relapsed in all the mice within administration period. Therapeutic administration of FTY720 (0.03 to 1 mg/kg) significantly improved the symptoms of chronic EAE induced by myelin oligodendrocyte glycoprotein in C57BL/6 mice whereas rm-IFN-β (10,000 IU/mouse) showed no clear effect. These results indicate that FTY720 is more efficacious in mouse EAE as compared with rm-IFN-β. FTY720 markedly reduced the frequency of PLP-specific Th17 and Th1 cells in the spinal cord of EAE mice. On the contrary, FTY720 increased the frequency of PLP-specific Th17 and Th1 cells in the inguinal lymph nodes, suggesting inhibition of egress of myelin antigen-specific Th cells from draining lymph nodes. From these results, the ameliorating effects of FTY720 on EAE are likely due to reduction of infiltration of myelin antigen-specific Th17 and Th1 cells into the central nervous system.
Chiba
Kenji
K
Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, 227-0033, Japan. Chiba.Kenji@mk.mt-pharma.co.jp
Kataoka
Hirotoshi
H
Seki
Noriyasu
N
Shimano
Kyoko
K
Koyama
Mamoru
M
Fukunari
Atsushi
A
Sugahara
Kunio
K
Sugita
Takahisa
T
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D000068876:Fingolimod Hydrochloride; D007155:Immunologic Factors / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018991:Myelin Proteolipid Protein / Q000633:toxicity; D011409:Propylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; D011409:Propylene Glycols; D016899:Interferon-beta; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine