FACTORS INVOLVED IN REJECTION OF CONCORDANT XENOGRAFTS IN COMPLEMENT-DEFICIENT RATS

Background. Factors that contribute to xenograft (Xg) rejection were i nvestigated in complement C6-deficient (C-) PVG rats. Methods. First a nd second hamster hearts were transplanted in CG-deficient and CG-suff icient PVG rats, Xenoantibody (XAb) formation, hemolytic C (CH50) acti vity and immunohistochemistry were studied. Results. PVG C6-deficient rats rejected Xgs 3 days later than PVG C6-sufficient rats, Surprising ly, C activation participated in the rejection in PVG C- rats, as show n by partially recovered serum CH50 levels and deposition of C factors in the Xgs. As we found that cultured endothelial cells produced C6 i n vitro, we hypothesized that Xg endothelial cells corrected the C6 de fect in PVG C- rats. This was probably induced by IgM XAbs as: (1) it did not occur in immunosuppressed PVG C- rats in which XAb formation w as prevented, and (2) transfer of IgM XAbs to naive, xenotransplanted PVG C- rats accelerated the recovery of CH50 and concomitantly Xg reje ction, Thirty days after rejection of a first Xg, when no IgM XAbs or CH50 activity but high levels of IgG XAbs were detected in PVG C- rats , second Xgs underwent a hyperacute rejection, This time, complement w as not involved, as no serum CH50 nor C deposition was found in the Xg , Instead, IgG antibody-dependent cellular cytotoxicity was involved a s: (1) IgG; XAbs were deposited in the Xg and (2) hy-peracute rejectio n was induced in naive PVG C- rats by transfer of IgG XAbs, and (3) th is rejection was delayed to 5+/-3 days if the adoptive hosts were firs t irradiated. Conclusions. In the face of a defect of host C factors, IgM XAb may induce cells of the Xg to secrete C factors which may corr ect the C defect of the host. Even if activation of lytic C can be pre vented, IgG XAb may still provoke an acute Xg rejection by antibody-de pendent cellular cytotoxicity.