KIDNEYS DERIVED FROM MICE TRANSGENIC FOR HUMAN-COMPLEMENT BLOCKERS ARE PROTECTED IN AN IN-VIVO MODEL OF HYPERACUTE REJECTION

Purpose: The major obstacle to successful discordant kidney xenotransp lantation is hyperacute rejection (HAR). Complement plays a key role i n the induction of HRA, defined by endothelial cell activation, loss o f vascular integrity, hemorrhage and thrombosis. The activation of com plement is tightly controlled by a number of species-specific regulato ry proteins which inhibit, at different points, the cascade of events leading to the formation of the membrane attack complex (MAC). We have tested the hypothesis that kidneys derived from transgenic mice expre ssing two human complement inhibitors, Decay Accelerating Factor (hDAF ) and Membrane Cofactor Protein (MCP), could be protected from human c omplement-mediated damage. Materials and Methods: Control and transgen ic mice were perfused with human plasma by cannulation of the right ju gular vein, at a perfusion rate of 10 mu L./min. for two hours. Comple ment C3 deposition was detected on kidney sections by immunohistochemi stry using specific FITC antibody. Complement-induced tissue damage wa s evaluated by histopathological examination. Results: Heavy depositio n of complement C3 was observed on kidneys derived from perfused contr ol mice. This was associated with a characteristic HAR pathology of se vere interstitial hemorrhage, inflammatory reaction, loss of glomerula and tubuli structure. Kidneys derived from mice transgenic for hDAF o r hMCP were partially protected from both complement C3 deposition and tissue damage. The expression of both hDAF and hMCP in double transge nic mice significantly increases the protection from human complement- mediated damage. Conclusion: A novel model of in vivo perfusion with h uman plasma has been adopted to recreate the initial event of HAR. Our data show that this murine model could be very valuable to determine the effect of transgenic human molecules in protecting vascularized or gans from human complement attack.