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Hamster to rat cardiac xenografts undergo delayed rejection as compared with the hyperacute rejection of discordant xenografts. Elicited xenoreactive Abs (EXA) are thought to initiate hamster to rat cardiac xenograft rejection. In this study, we demonstrate that following transplantation of a hamster heart, rats generated high levels of EXA. Adoptive transfer into naive recipients of purified IgM, IgG2b, or IgG2c, but not IgG1 or IgG2a EXA, induced xenograft rejection in a complement-dependent manner. Ability of EXA to cause rejection correlated with complement activation, platelet aggregation, and P-selectin expression in the xenograft endothelium. Cyclosporin A (CyA) administration, after transplantation, totally suppressed IgG1, IgG2a, IgG2b, and IgG2c EXA, and inhibited IgM EXA production, but failed to overcome rejection. Administration of cobra venom factor (CVF), 1 day before and at the time of transplantation, resulted in complement inhibition during 3 days after transplantation, which failed to overcome rejection. Combination of CyA and CVF, which we have previously shown to overcome rejection, resulted in suppression of IgG EXA production and in the return of IgM XNA to preimmunization serum levels, 3 to 7 days after xenotransplantation, while complement remained inhibited. Thus, under CyA/CVF treatment, complement activation by hamster cells was suppressed following xenotransplantation, and presumably for this reason xenograft rejection did not occur. In conclusion, our data demonstrate that EXA play a pivotal role in the pathogenesis of xenograft rejection and that CyA and CVF suppress xenograft rejection by preventing exposure of xenograft endothelial cells to complement activation by EXA.

Endothelial cell ATP diphosphohydrolases or ATPDases degrade extracellular inflammatory mediators ATP and ADP, thus inhibiting the formation of platelet thrombi, but the modulation of these ecto-enzymes during vascular injury remains largely undetermined. Renal glomerular ATPDase levels were determined in the rat following ischemia-reperfusion or systemic complement activation, by direct biochemical methods and histochemistry. Ischemia followed by reperfusion times over 30 min were associated with loss of glomerular ATPDase activity. Cobra Venom Factor (CVF) inhibited ATPDase activity and potentiated the deleterious effects of reperfusion. Treatment with either soluble complement receptor type 1 (sCR1), an inhibitor of complement activation, or antioxidants prior to the ischemia-reperfusion was largely protective. Expression of rat glomerular ATPDase activity appears susceptible to the inflammatory injury associated with systemic complement activation and ischemia/reperfusion processes. Oxidative stress could, at least in part, result in the loss of ATPDase activity and thus thrombotic consequences of vascular injury.