THE IMMUNOPATHOLOGY OF CARDIAC XENOGRAFT REJECTION IN THE GUINEA-PIG TO RAT MODEL

The mechanisms underlying rejection by rats of vascularized guinea pig xenografts have been controversial. The aim of this study was to defi ne, using sequential immunopathologic analysis, the contributions of x enoreactive antibody, complement, and effector cells to the rejection of guinea pig cardiac xenografts by Lewis rats. In untreated recipient s, hyperacute rejection of guinea pig cardiac xenografts occurred in 2 0+/-10.2 min and was characterized by focal endothelial deposition of IgM and by diffuse deposition of C3. IgG was not localized to endothel ial surfaces, but was present in the same locations as albumin, sugges ting that the accumulation of IgG might reflect nonspecific leakage of plasma proteins from blood vessels. No polymorphonuclear or monocytic infiltrate was observed. Depletion from rats of xenoreactive antibody to undetectable levels prolonged the survival of guinea pig cardiac x enografts, but did not prevent hyperacute rejection; the rejected xeno grafts contained deposits of C3 along the microvasculature but no depo sits of IgM or IgG. No cellular infiltrate was observed. Depletion of complement with cobra venom factor prolonged the survival of xenograft s up to 96 hr. Xenograft tissues from complement-depleted animals had diffuse deposits of IgM along the microvasculature, but no detectable deposits of C3 or IgG were noted. Graft tissues obtained at various ti mes after transplantation into complement-depleted animals revealed ce llular infiltrates consisting of granulocytes, monocytes, and lymphocy tes, but few cells bearing an NK cell phenotype. Our findings are cons istent with the concept that complement activation is essential for th e hyperacute rejection of discordant xenografts, and that in this part icular model complement activation can proceed without the involvement of antibody. However, our findings also suggest that xenoreactive ant ibody contributes to hyperacute rejection and, along with effector cel ls, contributes to the later rejection of a xenograft when hyperacute rejection has been averted. Finally, we show that when hyperacute reje ction is avoided, a form of vascular rejection occurs in which certain of the pathologic features-i.e., interstitial hemorrhage, interstitia l edema, and thrombosis-are very similar to those observed in hyperacu te rejection. Whether this form of rejection is a delayed form of the process that leads to hyperacute rejection or a novel pathologic proce ss of graft rejection has yet to be determined.