A strategy for generating consistent long-term donor-specific tolerance to solid organ allografts.

Current triple drug immunosuppression while effective, increases the risk of opportunistic infection and lymphoproliferative disorders. An alternative strategy would be the generation of donor-specific tolerance with short-term treatment. The use of donor-specific transfusions (DST) with a single brief course of cyclosporine (CsA) and rapamycin (Rapa) has produced promising results in animal models, but falls short of uniform tolerance. It was hypothesized that a DST/CsA/Rapa protocol administered in the perioperative period and redosed at one month might improve on this success in the ACI to Lewis rat heterotopic cardiac transplant model. Recipients received no treatment (group 1), a 1 ml DST intravenously (i.v.) with CsA 10 mg/kg subcutaneously (s.c.) at D-1 and CsA 2.5 mg/kg DO6D+13 (group 2), DST/CsA as dosed above with intraperitoneally (i.p.) Rapa 1 mg/kg D+36D+7 (group 3), DST/CsA/Rapa as above with all components redosed at one month (group 4), DST/CsA/Rapa with only CsA and Rapa repeated (group 5), and DST/CsA/Rapa with CsA redosed and Rapa continued indefinitely (group 6). Comparison of permanent survival (longer than 200 days) between protocols revealed groups 4-6 were significantly greater than control groups 1-3. Donor specificity was verified in group 6, where three permanent survivors received a second cardiac allograft from a Buffalo rat donor and rejected these grafts almost as quickly as untreated strain pair matched controls 21 +/- 1 days vs 30.3 +/- 5 days. Animals from group 6 displayed a greatly reduced mixed lymphocyte response to ACI cells but not to third-party cells. The percentage of T cells producing cytokines was reduced and shifted toward Th-2 type cytokines (IL-4). Thus, a repeated cycle of this brief DST/CsA/Rapa treatment appears to generate consistent permanent graft survival (up to 91%) that exceeds previously studied tolerance inducation protocols and is donor specific.