Dominant role of complement in the hyperacute xenograft rejection reaction

Xenotransplantation in distantly related donor-recipient systems is rejected within minutes. According to present theories, hyperacute rejection is due to preformed antibodies. However, our results suggest that a nonimmunologic reaction plays a dominant role in the hyperacute rejection reaction. To analyze the hyperacute rejection reaction, a previously described model of isolated in vitro xenohemoperfusion was used in which rat kidneys were perfused with dog blood at constant pressure. Rejection criterion was cessation of xenograft perfusion flow rate with constant perfusion pressure and histologic findings of aggregation of thrombocytes and endothelial lesions. In our experimental approach, the donor kidney was perfused with separate cellular and humoral components of the recipient blood with redetection of the rejection activity in one of the recipient blood components. Each blood component was tested for preformed antibody before hemoperfusion. In control studies, xenoperfusion of rat kidneys with whole blood from the dog always resulted in hyperacute rejection. In contrast, allogenic perfusion with whole blood caused no rejection. In three groups, typical hyperacute rejection occurred. Perfusion with whole blood from newborn dogs; no preformed antibodies in vitro; perfusion with reactivated dog whole blood containing no preformed xenohemoagglutinating antibodies, which had been eliminated by adsorption, and perfusion with reactivated dog whole blood containing no preformed xenocomplement fixing antibodies also eliminated by adsorption, all resulted in hyperacute rejection. Whole blood from newborn dogs and reactivated, adsorbed antibody-free whole blood from dogs contained active complement. Perfusion of rat kidneys with heat decomplemented, antibody-containing or antibody-free dog blood showed no hyperacute rejection reaction. The addition of fresh complement to these last two groups resulted in typical hyperacute rejection.