COMPLEMENT-FIXING ELICITED ANTIBODIES ARE A MAJOR COMPONENT IN THE PATHOGENESIS OF XENOGRAFT REJECTION

Hamster to rat cardiac xenografts undergo delayed rejection as compare d with the hyperacute rejection of discordant xenografts. Elicited xen oreactive Abs (EXA) are thought to initiate hamster to rat cardiac xen ograft rejection, In this study, ne demonstrate that following transpl antation of a hamster heart, rats generated high levels of ESA, Adopti ve transfer into naive recipients of purified IgM, IgG2b, or IgG2c, bu t not IgG1 or IgG2a EXA, induced xenograft rejection in a complement-d ependent manner. Ability of EXA to cause rejection correlated with com plement 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 ESA production, but failed to overcome rejection, A dministration of cobra venom factor (CVF), 1 day before and at the tim e of transplantation, resulted in complement inhibition during 3 days after transplantation, which failed to overcome rejection, Combination of CSA and CVF, which we have previously shown to overcome rejection, resulted in suppr ession of IgG EXA production and in the return of I gM SNA to preimmunization serum levels, 3 to 7 days after xenotranspla ntation, while complement remained inhibited, Thus, under CgA/CVF trea tment, complement activation by hamster cells was suppressed following xenotransplantation and presumably for this reason xenograft rejectio n did not occur, In conclusion, our data demonstrate that EXA play a p ivotal role in the pathogenesis of xenograft rejection and that CyA an d CVF suppress xenograft rejection by preventing exposure of xenograft endothelial cells to complement activation by EXA.