TRANSIENT COMPLEMENT INHIBITION PLUS T-CELL IMMUNOSUPPRESSION INDUCESLONG-TERM SURVIVAL OF MOUSE-TO-RAT CARDIAC XENOGRAFTS

Background. The use of anti-B-cell and T cell immunosuppressive agents leads to only a few weeks' survival of mouse-to-rat cardiac xenograft s. Methods. BALB/c cardiac xenografts were transplanted to Lewis rats treated with cyclosporine (CsA) and/or cobra venom factor (CVF). Resul ts. CsA alone did not prolong xenograft survival (2.2+/-0.4 days), whe reas CVF alone led to minimal prolongation of survival (5.6+/-0.8 days ) as compared with nontreated recipients (2.4+/-0.5 days). The combina tion of CsA plus CVF, the latter given for either 2 days or ii days, r esulted in long-term survival of 14/16 hearts (>100 days), Production of IgM elicited xenoreactive antibodies (EXA) peaked on day 4 after tr ans plantation and decreased thereafter. Production of IgG EXA occurre d only in the control group, whereas, in the CsA/CVF-treated group, Ig G EXA were totally suppressed. Long-term surviving grafts showed (i) e xcellent preservation of morphology and minimal leukocyte infiltration , (ii) deposition of IgM, IgG and weak C3 deposition on the graft endo thelium, (iii) low level infiltration by rat macrophages, (iv) replace ment of mouse dendritic cells by class II+ rat macrophages, and (v) ex pression within endothelial and smooth muscle cells, macrophages, and myocytes of HO-1, a ''protective gene'' not seen in the rejected heart s. Conclusions. Our present findings suggest that longterm mouse-to-ra t cardiac xenograft survival is induced by temporary suppression of C activation and sustained T-cell suppression leading to inhibition of I gG EXA production, Florid expression of a protective gene (HO-1) may c ontribute to survival.