Efficacy of combining donor-specific presensitization with a simultaneous single injection of tacrolimus on pulmonary allografts.

BACKGROUND: We investigated the effects of combining donor-specific presensitization with a simultaneous injection of tacrolimus by use of a fully allogeneic rat lung allograft model. METHODS: Lungs from Brown Norway donor rats were orthotopically transplanted into Lewis recipient rats. Seven days before transplantation, allograft recipients received a transfusion of donor splenocytes (1 x 10(8) cells, intravenously), tacrolimus (3 or 1.5 mg/kg, intramuscularly), or a combination. No posttransplantation immunosuppression was given. In the transplantation study, graft survival was evaluated, and histologic characteristics of acute rejection were graded. In the in vitro studies, mixed lymphocyte reaction assays were used to investigate the effects of pretreatment on immune response. RESULTS: The graft survival evaluation disclosed that untreated rats rejected the allografts at 4.6 +/- 0.2 days. Donor splenocyte transfusion alone accelerated the graft rejection (3.3 +/- 0.2 days). Tacrolimus (3 mg/kg) alone moderately improved the graft survival (8.7 +/- 0.6 days). When donor splenocyte transfusion was combined with tacrolimus, graft survival was significantly increased to 29.6 +/- 12.0 days. In a mixed lymphocyte reaction assay, peripheral blood lymphocytes obtained from animals pretreated with donor splenocyte transfusion alone seemed to be hyperresponsive against the donor lymphocytes. In contrast, donor splenocyte transfusion with tacrolimus significantly suppressed the proliferative response against the donor lymphocytes but not against third-party lymphocytes obtained from naive Wistar King A rats. CONCLUSION: These data demonstrate that donor-specific presensitization with a simultaneous single injection of tacrolimus prevented both sensitization and graft rejection and induced donor-specific unresponsiveness.