IMMUNOPATHOLOGY OF HYPERACUTE XENOGRAFT REJECTION IN A SWINE-TO-PRIMATE MODEL

TLDR

Hyperacute rejection inevitably occurs in vascularized organ transplants between phylogenetically distant species, yet the precise incompatibility mechanisms remain incompletely understood. The study aimed to elucidate these mechanisms through immunopathological analysis of swine renal and cardiac xenografts in rhesus monkeys. Tissue samples from the xenografts were examined for immune deposition, complement activation, and cellular infiltration to characterize the rejection process. Rejection was marked by recipient IgM and classic complement deposition on endothelial surfaces, platelet/fibrin thrombi, and neutrophil infiltration; depletion of natural antibodies delayed but did not prevent rejection, and prolonged grafts lacking complement activation showed IgM deposition without thrombi or neutrophils, indicating that rhesus IgM and complement fixation drive hyperacute rejection and coagulation cascade recruitment.

Abstract

Hyperacute rejection is the inevitable consequence of the transplantation of vascularized organs between phylogenetically distant species. The nature of the incompatibility and the pathogenetic mechanisms that lead to hyperacute xenograft rejection are incompletely understood. We investigated these issues by the immunopathological analysis of tissues from swine renal and cardiac xenografts placed in rhesus monkeys. Hyperacute rejection was associated with deposition of recipient IgM and classic but not alternative complement pathway components along endothelial surfaces, the formation of platelet and fibrin thrombi, and the infiltration of neutrophils. In animals from which natural antibody was temporarily depleted by organ perfusion, rejection was observed at 3 days to 5 days posttransplant. The immunopathology of rejection in these tissues revealed focal vascular changes similar to those observed in hyperacute rejection. A xenograft functioning for a prolonged period in a recipient temporarily depleted of circulating natural antibody contained recipient IgM along endothelial surfaces but no evidence for significant deposition of complement, formation of platelet and fibrin thrombi, or infiltration of neutrophils. These results suggest that rhesus IgM contributes significantly to the development of hyperacute rejection in the swine to Rhesus model and that the fixation of complement is a critical factor in the recruitment of the coagulation cascade and platelet aggregation--and possibly in the adherence and infiltration of PMN.