EVIDENCE THAT DONOR PRETREATMENT WITH FK506 HAS A SYNERGISTIC EFFECT ON GRAFT PROLONGATION IN HAMSTER-TO-RAT HEART XENOTRANSPLANTATION

Background: Concordant xenografts are rejected in a different fashion than are discordant xenografts or allografts. We tested the effect of donor pretreatment with the use of FK506 combined with posttransplanta tion FK506 treatment and splenectomy and analyzed the mechanism of rej ection in hamster-to-rat heart xenotransplantation. Methods: Heart xen otransplantation from hamster to rat was carried out under immunosuppr ession with the use of donor pretreatment with FK506, posttransplantat ion FK506 treatment and splenectomy, followed by complement-dependent cytotoxicity assay, delayed type hypersensitivity test, and histologic analysis. Results: The cardiac graft survived 3 days without donor pr etreatment, whereas it survived 4.8 days with donor pretreatment with FK506 (5 mg/kg for 3 days). The graft survival was synergistically enh anced by donor pretreatment, posttransplantation FK506 therapy, and sp lenectomy, and the longest survival was 43.6 +/- 7.7 days in the group with donor pretreatment, posttransplantation FK506 therapy for 4 week s, and splenectomy. Delayed-type hypersensitivity response was suppres sed significantly in the donor pretreatment group. The antibody typed by immunoglobulin M was mainly detected in the rat serum with the reje cted grafts by complement-dependent cytotoxicity assay. Correlating wi th this complement-dependent cytotoxicity titer, neutrophil infiltrati on and vasculitis of the coronary vessels were recognized in the rejec ted grafts, and the marginal zone of the white pulp expanded in the sp leen. Conclusions: Donor pretreatment with FK506 combined with posttra nsplantation FK506 therapy and splenectomy suppresses the outlet antig en, immunoglobulin M production, and lymphocyte activation, thereby pr olonging the graft survival in hamster-to-rat heart xenotransplantatio n.