| Co-Investigator(Kenkyū-buntansha) |
KAKEFUDA Toshihiro National Children's Medical Research Center, 小児医療研究センター・実験外科生体工学部, 研究員
SHINOMIYA Takahisa National Children's Medical Research Center, 小児医療研究センター・共同利用研究室, 室長 (30196414)
ENOSAWA Shin National Children's Medical Research Center, 小児医療研究センター・実験外科生体工学部, 室長 (40232962)
TAMURA Akihiko National Children's Medical Research Center, 小児医療研究センター・実験外科生体工学部, 研究員
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| Research Abstract |
FTY720 is a chemical substance derived by modifying an immunosuppressive metabolite, ISP- 1 from Isaria sinclairii, an ascomycete. Its chemical structure is completely different from conventional immunosuppressants. The in vivo administration of a single dose of FTY720 at 10 mg/kg caused a profound and long-lasting decrease in peripheral lymphocytes in rats. We found it of particular interest that we observed with electron microscopy that rat spleen cells incubated with FTY720 had features characteristic of apoptosis. The induction of apoptosis seems to occur specifically in the lymphocyte population. We administered FTY720 to the MRL-lpr/lpr mice, Fas-mutant mice, resulting in a significantly prolonged survival. We found a large number of apoptotic cells in the thymus, spleen and lymph nodes. We also found that FTY720 displays bcl-2-associated apoptotic cell death. The administration of FTY720 to liver-allografted rats resulted in a marked increase in the survival of the recipients, with no adverse reaction to the drug. The preclinical study was conducted to define an effective range of FTY720 to be combined with a suboptimal dose of cyclosporin (CsA) in randomized, mongrel-to-beagle, canine kidney recipients. The combination with CSA significantly prolonged graft and recipient survivals. Therefore, we concluded that FTY720 has a potent effect at an extremely low dosage and a wide therapeutic window when combined with CsA, even in a large animal model. From these results, FTY720 remains a promising drug for clinical application in the field of organ transplantation.
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