Discordant liver transplantation in the guinea pig to rat model does not lead to classical hyperacute rejection

Abstract: Discordant grafting, the best alternative for future transplantation, is hampered by hyperacute rejection (HAR). Yet, there might be a difference in susceptibility to HAR between organs. In allogeneic transplantation the liver is less sensitive to antibody mediated rejection. In order to investigate whether this might also occur in discordant xenotransplantation, we performed orthotopic liver transplantation (OLT) from Dunkin Hartley guinea pigs (GP) to Brown Norway rats. Five groups were studied. In group 1, untreated controls survived for 1.5 to 4.5 hr (n = 5). In order to investigate how long a recipient could survive without a functioning graft, animals in group 2 underwent total hepatectomy (tHx) with portal-caval shunt, resulting in survival times ranging from 2 to 7 hr (n = 5). Antibody reduction by splenectomy (Spx) on day -5 (group 3) did not increase survival time (1 to 2 hr, n = 5). Complement depletion by cobra venom factor (CVF) prolonged the survival time up to 35 hr (n = 7, group 4). One animal lived for 4 days. The combined treatment of Spx and CVF resulted in similar survival times as following CVF alone, ranging from 2 hr to 6 days (n = 6, group 5). Surprisingly, none of the grafts in either of the groups showed classical signs of hyperacute rejection, like hemorrhage, edema, or obstruction of capillaries and veins as seen in the GP to rat heart transplantation model. Also liver enzyme parameters indicated no ongoing rejection. Immunohistochemistry revealed deposits of complement factors C1q, C3, and C6 on Kupffer cells but not on endothelial cells. These results indicate that, in this particular discordant model, the liver is not affected by the classical features of HAR. The beneficial effect of CVF on recipient survival therefore may rather be due to inhibition of a lethal secondary response evoked by the graft than to inhibition of HAR.