Induction of lymphocyte apoptosis in rat liver allograft with ongoing rejection by FTY720

The action mechanism of FTY720, a novel immunosuppressant, is completely di fferent from conventional immunosuppressants. The drug, which triggers apop tosis in murine and human lymphocytes, has a potent immunosuppressive activ ity to prevent allograft rejection without any severe side-effect. The pres ent study was designed to determine whether FTY720 induces apoptotic cell d eath in activated lymphocytes infiltrated into liver grafts with ongoing re jection. FTY720 was orally administered at 5 mg/kg to the recipients on day 3 and day 4 after grafting, when the graft rejection was histologically co nfirmed. The intragraft patterns of IL-2, interferon-gamma (IFN-gamma), per forin, and granzyme B gene expression were detected by reverse transcriptas e-polymerase chain reaction. The treatment reversed ongoing rejection and s ignificantly prolonged recipient survival time compared with the control gr oup. Light microscopic observation of the graft sections stained with the D NA nick-end labelling method showed that the apoptosis in the control allog rafts was mainly induced in hepatocytes, while that in the FTY720-treated a llografts was in infiltrated lymphocytes. The rejection therapy with FTY720 did not alter the expression of IL-2, IFN-gamma, and perforin mRNAs, but s lightly decreased granzyme B expression. Our results suggest that FTY720 do es not alter the intrinsic lymphocyte function to produce the rejection-rel ated cytokines, but strongly induces apoptotic cell death in the activated lymphocytes. Thus, FTY720 affords new insight into the mechanisms underlyin g improvements in immunosuppressive treatments.