Sphingosine 1-phosphate receptor modulator, fingolimod (FTY720), provides a new therapeutic approach for autoimmune diseases

DOI Web Site 参考文献33件
  • Chiba Kenji
    Pharmacology Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
  • Kataoka Hirotoshi
    Pharmacology Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
  • Maeda Yasuhiro
    Pharmacology Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
  • Seki Noriyasu
    Pharmacology Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
  • Sugahara Kunio
    Pharmacology Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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FTY720 (Fingolimod) is the first of a new immunomodulator class: sphingosine 1-phosphate (S1P) receptor modulator. We have found FTY720 by chemical modification of a natural product, myriocin derived from Isaria sinclairii, a kind of vegetative wasp. FTY720 is orally active and is highly effective in various autoimmune disease models including experimental autoimmune encephalomyelitis (EAE), adjuvant- or collagen-induced arthritis, and lupus nephritis. Particularly, oral administration of FTY720 shows marked therapeutic effects on EAE in mice with a significant reduction of demyelination and T cell infiltration in the central nervous system. A most striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating effects. It is revealed that the reduction of circulating lymphocytes by FTY720 is due to sequestration of lymphocytes into secondary lymphoid organs. FTY720 is rapidly converted to FTY720-phosphate (FTY720-P) by sphingosine kinases. FTY720-P acts as a potent agonist at S1P receptor type 1 (S1P1), internalizes S1P1 on lymphocytes, and inhibits migration of lymphocytes toward S1P. It is highly likely that immunomodulating effects of FTY720 are caused by inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid organs. Moreover, it is suggested that direct effects of FTY720-P on neural cells via S1P receptors promote neuroprotection. Since FTY720 possesses a novel mechanism of action and is highly effective in relapsing remitting multiple sclerosis patients, it is presumed that oral FTY720 provides a new therapeutic approach for autoimmune diseases including multiple sclerosis.

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