Accommodated xenografts survive in the presence of anti-donor antibodies and complement that precipitate rejection of naive xenografts

Hamster hearts transplanted into transiently complement-depleted and contin uously cyclosporin A (CyA)-immunosuppressed rats survive long-term despite deposition of anti-donor IgM Abs and complement on the graft vascular endot helium. This phenomenon is referred to as "accommodation." The hypothesis t ested here is that accommodated xenografts are resistant to IgM Abs and com plement that could result in rejection of naive xenografts, After first ham ster hearts had been surviving in cobra venom factor (CVF) + CyA-treated ra ts for 10 days, a time when the anti-donor IgM Ab level was maximal and com plement activity had returned to approximately 50% of pretreatment levels, naive hamster hearts or hamster hearts that had been accommodating in anoth er rat for 14 days were transplanted into those rats carrying the surviving first graft. The naive hearts were all hyperacutely rejected, In contrast, a majority of regrafted accommodating hearts survived long-term, There was widespread Ab and activated complement deposition on the vascular endothel ium of accommodating first hearts, second accommodating hearts, and rejecte d second naive hearts. However, only the rejected naive hearts showed exten sive endothelial cell damage, myocardial necrosis, fibrin deposition, and o ther signs of inflammation, Accommodating first and second hearts but not r ejected second naive hearts expressed high levels of the protective genes A 20, heme oxygenase-l (HO-1), bcl-2, and bcl-x(L). These data demonstrate th at accommodated xenografts become resistant to effects of anti-donor IgM Ab s and complement that normally mediate rejection of xenografts, We hypothes ize that this resistance involves expression by accommodated xenografts of protective genes.