Effect of a novel immunosuppressant, FTY720, on allograft survival after renal transplant in rats

FTY720 was developed by chemical modification of ISP-1 which was purified f rom culture filtrates of an ascomycete, Isaria sinclairii. We evaluated the effect of FTY720 on allograft survival using a rat renal transplantation m odel in which Wistar King Aptekman Hokkaido rats (WKAH, RT1(K)) served as t he organ donor and Lewis rats (LEW, RT1(l)) as the recipient. WKAH renal al lografts were acutely rejected by the untreated LEW recipients at a mean gr aft survival +/- SD of 7.2 +/- 0.4 days (n = 5). Consecutive oral administr ation of FTY720 following transplantation significantly prolonged allograft survival in a dose-dependent manner over the range of 0.05-3 mg/kg/ day. T he mean allograft survival of the recipients treated with FTY720 at a doses of 0.05, 0.1, 0.5, 1, and 3 mg/kg/ day was 12.2 +/- 3.3 (n = 5, p < 0.05, vs. untreated host), 11.2 +/- 2.4 (n = 5, p < 0.05, vs. untreated host), 13 .6 +/- 0.9 (n = 5, p < 0.01, vs. untreated host), 14.6 +/- 1.7 (n = 5, p < 0.01, vs, untreated host) and 20.2 +/- 0.8 days (n = 5, p < 0.01, vs, untre ated host). In the recipients treated with FTY720 (3 mg/kg/day), the number of peripheral blood lymphocytes significantly decreased. From the results of the flow cytometric study, FTY720 significantly diminished the percentag e of interleukin-2 receptor (IL-2R)positive cells in the allografts (6.34 /- 0.81% in the untreated recipients vs. 3.10 +/- 0.86% in the recipients t reated with FTY720, p < 0.05). As to the CD4/CD8 ratio of splenic cells and graft infiltrate, there was no significant difference between the untreate d hosts and the recipients treated with FTY720. In conclusion, FTY720 signi ficantly extended rat renal allograft survival and the immunosuppressive ef fects of FTY720 may be due to a reduction in not only the number of periphe ral lymphocytes but also the percentage of IL-2R-positive cells in the allo grafts. Copyriht (C) 2000 S. Karser AG, Basel.