Effect of FTY720 on immunoregulation in concordant xenotransplantation.

Abstract

The present study was designed to analyze the immunosuppressive activity of FTY720 in concordant xenotransplantation. When T and B lymphocytes of human peripheral blood were incubated with FTY720, the number of viable cells decreased in a dose-dependent manner at doses higher than 4 x 10(-5) M. DNA fragmentation was observed at doses higher than 1 x 10(-5) M in T cell-rich fractions and at doses higher than 4 x 10(-5) M in B cell-rich fractions. These data demonstrate that FTY720 is cytotoxic to B lymphocytes as well as T lymphocytes and apoptosis may play an important role in this cytotoxicity. Golden Syrian hamsters were the donors and Lewis rats the recipients of skin grafts. The recipients were divided into the following four groups: (1) untreated recipients, (2) FTY720 (5 mg/kg per day) was administered orally for 8 days (days-1-6), (3) FK506 (1 mg/kg per day) was injected i.m. for 7 days (days 0-6), and (4) FK506 (1 mg/kg per day) was injected i.m. for 7 days (days 0-6) and FTY720 (5 mg/kg per day) was administered orally for 8 days (days-1-6). The mean graft survival times in groups 1-4 were 9.7 +/- 0.52 days (n = 6), 12.0 +/- 0.71 days (n = 6), 13.2 +/- 1.6 days (n = 6), and 37.7 +/- 4.3 days (n = 6), respectively. There was a significant difference in the mean survival time between groups one and four. Combined therapy with FTY720 and FK506 is a useful tool for immunoregulation in xenotransplantation.