USE OF THE METHYLXANTHINE DERIVATIVE A802715 IN TRANSPLANTATION IMMUNOLOGY .2. IN-VIVO EXPERIMENTS

Background, We have previously demonstrated in vitro that the methylxa nthine derivative A802715 suppresses the cyclosporine (CsA)-resistant ''signal two''-dependent pathway of T cell activation and hence acts s ynergistically with CsA. Here, this synergism was further investigated in vivo in rats. Methods. Primary cardiac allografts were placed in t he neck, and secondary grafts were transplanted intra-abdominally, A80 2715 was given orally for 30 days or by continuous intravenous infusio n via a mini-osmotic pump for 2 weeks, CsA was given orally for up to 30 days, T cell responses were examined in vitro using mixed lymphocyt e reaction, concanavalin A whole blood, and cell-mediated lympholysis assays. Results. In a major histocompatibility complex incompatible WK AH-->PVG combination, neither oral CsA (7.5 mg/kg/day) nor oral A80271 5 (100 mg/kg/day) was able to prolong graft survival, However, a combi nation of both drugs, given at the same dose, sustained graft survival during treatment, A similar synergism was not obtained with pentoxify lline, another methylxanthine derivative. The synergism between A80271 5 and CsA could be further increased by using a continuous intravenous infusion of A802715, since (1) lower doses of A802715 (20 mg/kg/day) and CsA (5 mg/kg/day) could be used, and (2) six of seven grafts survi ved permanently, In a major histocompatibility complex compatible Wag/ Rij-->R/A combination, similar synergistic effects and permanent graft survival could also be obtained by oral A802715 (100 mg/kg/day) in co mbination with a low dose of CsA (2.5 mg/kg/day), In both strain combi nations, long-term survivors accepted donor-type but rejected third-pa rty second grafts in the absence of immunosuppression. This specific t olerance was not related to clonal deletion nor anergy, as recipient l ymphocytes proliferated normally in the anti-donor mixed lymphocyte re action, Instead, a defect in generating specific cytotoxic T lymphocyt es was involved. Conclusions. A802715 synergizes with CsA in vivo to i nduce specific transplantation tolerance and hence should be considere d as a promising new immunosuppressant.