TOWARD NOVEL ANTIREJECTION STRATEGIES - IN-VIVO IMMUNOSUPPRESSIVE PROPERTIES OF CTLA4IG

Allograft rejection is a process that depends on T cell receptor-ligand interaction and costimulatory signals generated when accessory molecules binds to their ligands, such as CD28 to the B7 molecules. We investigated the possibility that B7 blockade in vivo by the soluble CD28 receptor homolog CTLA4Ig modulates rejection process in a rat model of kidney allograft. Lewis rats orthotopically transplanted with MHC incompatible kidney from Brown-Norway rats were given an intraperitoneal injection of CTLA4Ig (0.2 or 0.5 mg/day) or a nonspecific immunoglobulin for seven days, starting the day of transplant. While control rats rejected the graft within 10 days, all animals given CTLA4Ig had a prolonged kidney allograft survival, independently from the dose of the fusion protein employed. Actually, at the dose of 0.2 mg/day kidney grafts survived 36 to 50 days (median 44 days), while with the highest dose graft survival was 40 to 60 days (median 50 days). In all CTLA4Ig-treated rats renal grafts were well functioning as documented by serum creatinine concentrations comparable to age- and sex-matched control rats 30 days after transplant. At this time in vitro mixed lymphocyte culture (MLR) experiments showed a significant reduction of proliferation of peripheral blood lymphocytes from CTLA4Ig-treated rats when challenged with BN but not third party Wistar Furth lymphocytes. We have also shown that combining a short course of CTLA4Ig (0.2 mg/day) with a dose of cyclosporine (CsA) low enough to fail to inhibit graft rejection allowed indefinite engraftment of kidney allograft without the need of continuous immunosuppression. In these animals the in vitro MLR proliferative response to BN donor lymphocytes was significantly reduced as compared to controls. These findings show that long-term unresponsiveness to kidney allograft can be achieved even with a short course of combined administration of CTLA4Ig with low dose CsA at least in rats.