Immunosuppressive therapy using FTY720 combined with tacrolimus in rat liver transplantation

Abstract

Background: FTY720 (FTY) exerts its effects through a reduction of peripheral lymphocytes. This unique mechanism allows for a possible combination effect with other immunosuppressants. We investigated therapy with FTY combined with tacrolimus (FK) in rat liver transplantation.

Methods: Different doses of FK, FTY, or both were orally administered to the recipients for 15 days. Expression of cytokine mRNAs using RT-PCR and appearance of lymphocyte apoptosis by immunohistologic staining were studied in the allografts.

Results: Recipients treated with a low dose of FK (0.3 mg/kg) or FTY (0.03 mg/kg) showed a slightly prolonged survival time, although combination therapy with these drugs prolonged survival time similar to the duration obtained by an optimal dose of each drug alone. A marked suppression of lymphocyte infiltration and decreased levels of mRNAs for IL-2, IFN-gamma, and granzyme B were seen in the grafts with combination therapy. Grafts with combination therapy showed an increased number of cells double-stained with TUNEL and CD2 in infiltrated lymphocytes.

Conclusions: Allografts that underwent combination therapy demonstrated markedly reduced lymphocyte infiltration; a number of cells had induced apoptosis and an inhibition of IL-2, IFN-gamma, and granzyme B mRNA transcription, but not IL-4 and IL-10 transcripts, accounting for powerful mutual effect of FTY and FK.