PROLONGED DISCORDANT XENOGRAFT SURVIVAL AND DELAYED XENOGRAFT REJECTION IN A PIG-TO-BABOON ORTHOTOPIC CARDIAC XENOGRAFT MODEL

Objective: Our objectives were to study delayed xenograft rejection an d the effectiveness of pretransplantation total lymphoid irradiation c ombined with immunosuppression on rejection in a Dig-to-baboon cardiac xenograft model, Methods: Baboons were treated with pretransplantatio n total lymphoid irradiation, cyclosporine A (INN: ciclosporin), and m ethotrexate. Orthotopic pig-to-baboon cardiac transplantations were pe rformed after depletion of circulating xenoreactive natural antibody b y pretransplantation donor organ hemoperfusion. Tissue samples were co llected for immunologic and immunopathologic evaluation. Results: Pig cardiac xenografts survived more than 18 and 19 days without evidence of hyperacute rejection. Immunologic analysis of serum samples demonst rated that circulating xenoreactive natural antibody levels did not re turn to pretransplantation levels, The production of xenoreactive natu ral antibodies from the recipient's splenocytes was inhibited complete ly. Histologic examination of xenografts showed the feature of acute v ascular rejection, Immunohistochemical studies demonstrated infiltrati on of cardiac xenografts by large numbers of macrophages, small number s of natural killer cells, and a few T cells. The infiltrating macroph ages also showed expression of interleukin-1 and tumor necrosis factor , Diffuse deposition of immunoglobulin G, C1Q, C3, and fibrin on xenog raft vasculature was observed. Interleukin-2 expression was not found in rejected cardiac xenografts, Xenograft endothelial cells also showe d evidence of activation (expression of cytokines interleukin-1 and tu mor necrosis factor). Conclusions: This study demonstrates prolonged d iscordant cardiac xenograft survival and delayed xenograft rejection i n a pig-to-baboon model, The delayed xenograft rejection is mediated b y both humoral and cellular mechanisms, Pretransplantation total lymph oid irradiation combined with cyclosporine A and methotrexate can inhi bit xenoreactive natural antibody production but not elicited antipig antibody production and the xenoreactivity of macrophages.