Delayed cardiac xenograft rejection in a pig-to-baboon model treated with a tolerance-inducing regimen and donor bone marrow infusion

Abstract

DISCORDANT cardiac xenografts are hyperacutely rejected owing to the binding of natural antibody (NAb) to xenograft endothelial cells and activation of the complement pathway. Depletion of NAb and complement from recipients can prevent hyperacute rejection. However, delayed xenograft rejection (DXR) has become a major barrier to long-term xenograft survival after overcoming hyperacute rejection. The pathogenesis of DXR has been demonstrated to be macrophage-mediated cellular rejection and newly developed NAb. Total lymphoid irradiation (TLI) has been used as a conditioning regimen for bone marrow transplantation, a treatment designed to remove or suppress peripheral T and B cells while leaving bone marrow stem cells intact. TLI has been shown, with some success, to induce specific transplant tolerance to allografts and xenografts. Our previous study has shown alteration of humoral immune response in a rhesus monkey-to-baboon cardiac xenograft model treated with methotrexate and cyclosporine A. In this study, we utilized TIL combined with immunosuppression of humoral immunity by methotrexate to establish donor bone marrow engraftment and immune tolerance, and to prevent DXR in a pig-to-baboon cardiac xenograft model.