These results indicate that, after Tx, the contractile property of rat aorta allografts is altered before manifest vascular remodeling. Because this can be prevented by cyclosporine, it most likely reflects an acute rejection of SMC. These results also show that vascular graft dysfunction can be used to monitor the development of rejection in the rat aorta allograft model.
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.
In order to study the contribution of extrahepatic C6 to anti-Thy1.1 nephritis, C6 deficient PVG/c- livers were grafted in C6 sufficient PVG/c+ rats (Tx-L). Infusion of anti-Thy1.1 antibodies in Tx-L and PVG/c+ rats resulted in generation of C5b-9 complexes and subsequent glomerular injury, while infusion of anti-Thy1.1 antibodies in PVG/c- rats revealed no detectable C6 deposition. Because C6 mRNA was expressed in both liver and kidney tissue of PVG/c+ rats, we assessed whether production of C6 in the kidney alone was sufficient for glomerular injury. One kidney of a PVG/c- rat was replaced with a PVG/c+ kidney (Tx + K) followed by administration of anti-Thy1.1 antibodies. C6 deposits were detectable neither in PVG/c+ kidneys nor in PVG/c- kidneys of Tx + K rats, indicating that C6 production in PVG/c+ kidneys alone is not sufficient to contribute to renal injury. That C6 production had occurred was suggested by the presence of equal amounts C6 mRNA in control PVG/c+ kidneys and in grafted PVG/c+ kidneys of Tx + K rats. C6 mRNA expression in kidney tissue of PVG/c+ rats is presumably derived from peritubular sites. In conclusion, we have demonstrated that extrahepatic, but not renal synthesis of, C6 is sufficient to contribute to glomerular injury during anti-Thy1.1 nephritis.
We reported previously that no classical features of hyperacute rejection (HAR) could be found in liver grafts in the guinea-pig (GP)-to-rat model and that recipients died shortly after transplantation of non-immunologic causes. Thus, the GP-to-rat model is not suitable for studying the mechanisms of discordant liver xenograft rejection. In the hamster to rat model, long-term survival of a liver graft is possible, but extremely low levels of xenoreactive natural antibodies are present. To mimic a discordant situation with pre-formed IgM and IgG antibodies, we sensitized rats 1 or 5 weeks before grafting. Specific anti-hamster IgM antibodies were found in recipients sensitized at week -1 but not week -5. Anti-hamster IgG was present in all recipients, albeit considerably higher in animals sensitized 5 weeks before grafting. In these two models, we examined the mechanism of HAR of liver grafts and compared this with heart xenografts. Control heart and liver grafts were rejected 4 and 7 days after transplantation respectively. Liver grafts in recipients sensitized at week -5 showed venous congestion and bleeding after reperfusion, indicating HAR, however this was not observed after sensitization at week -1. This surprising finding was confirmed by histology. Massive extravasation, edema, and acute liver cell degradation were noticed in grafts subjected to HAR. Liver grafts of recipients sensitized at week -1 showed only minimal changes. Heart grafts were rejected hyperacutely in both sensitization models. IgG antibodies could be detected on liver grafts in the group sensitized at week -5 but not in the group sensitized at week -1. Minimal IgM depositions were found on liver grafts of animals sensitized 1 week before grafting. Rejected heart grafts from similar sensitization groups showed identical antibody depositions; only IgM depositions were massive. Complement depositions were found in all groups. These results indicate that IgG, but not IgM, mediates HAR in hepatic xenografting. Such a predominance of IgG over IgM does not exist for heart grafts.
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