A NOVEL IMMUNOSUPPRESSANT, FTY720, WITH A UNIQUE MECHANISM OF ACTION,INDUCES LONG-TERM GRAFT ACCEPTANCE IN RAT AND DOG ALLOTRANSPLANTATION

A new compound with an immunosuppressive property was purified from cu lture filtrates of Isaria sinclairii and was chemically modified to FT Y720. Rat spleen cells incubated with FTY720 demonstrated features cha racteristic of apoptosis-such as the absence of surface microvilli, ch romatin condensation, and the formation of apoptotic bodies-by electro n microscopy, and genemic DNA fragmentation by agarose gel electrophor esis. When FTY720 was administered in liver-allografted rats at a dose of 0.5 mg/kg from day 1 to day 14 after transplantation, the recipien ts survived significantly longer than the control group. Pretransplant treatment with 5 mg/kg of FTY720 one day before and on the day of gra fting induced a remarkable prolongation of recipient survival, and thr ee of 10 recipients survived for longer than 50 days. Furthermore, adm inistration of FTY720 at 5 mg/kg on days 3 and day 4 after grafting al so prolonged survival. In canine kidney allografting, a pretransplant 2-day course of FTY720 at 5 mg/kg prolonged graft survival. Daily admi nistration of FTY720 in combination with CsA resulted in a significant prolongation of graft survival in a synergistic manner. In addition, FTY720 appeared to be nontoxic in canine recipients. These results dem onstrated that FTY720, having a unique mechanism of action, induces lo ng-term graft acceptance in rat and dog allotransplantation.