In the pig-to-human combination, HAR occurs within minutes to hours of engraftment. It is initiated when PNXAb binding to antigens on the endothelial cell activate the classical pathway of the complement cascade. Activation of the classical pathway in turn allows for subsequent recruitment of the complement alternative pathway. As a result, several biologically active complement fragments complex (membrane attack complexes, MAC). These products of complement activation may play significant roles in vascular injury by inducing an increase in vascular permeability (C3a, C5a)-contributing to development of a procoagulant state (MAC), promoting cell adhesion (C3bi), or inducing direct endothelial cell damage (MAC).

Studies in primates support a process wherein complement-fixing PNXAb of the IgM isotype are thought to initiate HAR of porcine organs.

The severity of hyperacute rejection results in part from failure of membrane-associated regulators of complement in the donor organ to inhibit the activation of the recipient complement system. These regulators of complement activation (RCA) are known to be inhibitory only for homologous complement for complement of a closely related species and-not for complement of distantly related species. Thus, pig RCA fail to inhibit activation of human complement. Incorporation of recipient RCA into the vascular endothelium of the xenogeneic donor organ could allow for marked inhibition of recipient complement activation, with an associated impact on HAR. In vitro studies where genes for human RCA have been introduced into xenogeneic cells have demonstrated the feasibility and cytoprotective effects of this approach. Using transgenic technology, expression of human RCA in porcine organs has been achieved, with significant prevention of HAR.

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