DELAYED XENOGRAFT RESECTION OF PIG-TO-BABOON CARDIAC TRANSPLANTS AFTER COBRA VENOM FACTOR THERAPY

Background. This study sought to (i) investigate the efficacy of cobra venom factor (CVF) in preventing hyperacute rejection (HAR) after pig -to-baboon heart transplantation, (ii) examine the effect of additiona l splenectomy (Spx) and pharmacologic immunosuppression (IS), and (iii ) study delayed graft rejection when HAR is avoided by complement depl etion. Methods. Eleven recipient baboons received heterotopic pig hear t transplants. Three received either no therapy or IS (cyclosporine methylprednisolone +/- cyclophosphamide +/- methotrexate) at clinicall y well-tolerated doses, with graft survival for only 40, 32, and 15 mi n, respectively. Two received CVF+/-Spx, which extended survival to 5 and 6 days, respectively. Six underwent Spx + CVF therapy + IS; graft survival was 3 hr (technical complication), 6 days (death from sepsis) , 10, 12, and 22 days (vascular rejection), and <25 days (euthanized f or viral pneumonia with a functioning graft that showed histopathologi c features of vascular rejection). Results. Dense deposition of IgM an d, to a lesser extent, IgG and IgA were seen on the endothelial cells within 1 hr of transplantation, but only trace levels of complement de position were present in CVF-treated recipients. Within approximately 5-12 days, cardiac xenografts showed progressive infiltration by monon uclear cells, consisting primarily of activated macrophages producing tumor necrosis factor-alpha and small numbers of natural killer cells; T and B cells were absent. Conclusions. We conclude that (i) CVF prev ents HAR, (ii) the addition of Spx + IS delays rejection, but (iii) th e early deposition of antibody leads to progressive graft injury, resu lting in (iv) delayed vascular rejection. Our findings indicate that t he features of delayed xenograft rejection described in small animal m odels also occur in the pig-to-baboon model, and that rejection may oc cur in a complement-independent manner from the effects of antibody an d/or host macrophages.