IMMUNOSUPPRESSIVE EFFECTS OF FTY720 ALONE OR IN COMBINATION WITH CYCLOSPORINE AND OR SIROLIMUS/

Background. We examined the ability of FTY720, a novel immunosuppressa nt that prolongs the survival of allografts in experimental animal mod els, to potentiate the immunosuppressive effects of cyclosporine (CsA) and/or sirolimus (SRL) in vitro and in vivo. Methods. FTY720 alone (1 0-5000 ng/ml) or in combination with other drugs was added to human pe ripheral blood lymphocytes (PBLs) undergoing stimulation in vitro with phytohemagglutinin (PHA) or OKT3 monoclonal antibody. The combination index (CI) values were calculated to evaluate the nature of the inter actions between FTY720 and CsA and/or SRL: CI values <1 reflect synerg istic, CI=1, additive, and CI>1, antagonistic interactions, In additio n, Wistar Furth (RT1(u)) rat recipients of Buffalo (RT1(b)) heart allo grafts were treated with FTY720 alone or in combination with other age nts. FTY720 alone was also tested to block small bowel or liver allogr aft rejection in rats. Results. FTY720 alone produced only modest inhi bition of the proliferation of human PBL stimulated with PHA or OKT3 m onoclonal antibody. In combination with CsA or SRL, however, FTY720 pr oduced synergistic effects, namely, CI values of 0.58 and 0.36, respec tively. A 14-day course of FTY720 (0.05-8.0 mg/kg/day) by oral gavage prolonged heart allograft survival in dose-dependent fashion. Although a 14-day oral course of CsA (1.0 mg/kg/day) alone was ineffective (me an survival time=7.0 +/- 0.7 vs, 6.4 +/- 0.6 days in treated vs, untre ated hosts), treatment with a combination of 1.0 mg/kg/day CsA and 0.1 mg/kg/day FTY720 extended allograft survival to 62.4 +/- 15.6 days (P <0.001; CI=0.15). Similarly, a 14-day oral course of 0.08 mg/kg/day SR L alone was ineffective (6.8 +/- 0.6 days; NS), but the combination of SRL with 0.5 mg/kg/day FTY720 extended the mean survival time to 34.4 +/- 8.8 days (CI=0.28), The CsA/SRL (0.5/0.08 mg/kg/day) combination acted synergistically with FTY720 (0.1 mg/kg/day) to prolong heart sur vivals to >60 days (CI=0.18). Conclusions. FTY720 potentiates the immu nosuppressive effects of CsA and/or SRL both in vitro (by inhibiting o f T-cell proliferative response) and in vivo (by inhibiting allograft rejection).