An in vivo model of hyperacute rejection: characterization and evaluation of the effect of transgenic human complement inhibitors

Hyperacute rejection (HAR) occurring after transplantation within phylogene tically distant species is a severe reaction triggered by preexisting xenor eactive antibodies and complement activation, leading to the destruction of the donor organ. Expression of human complement inhibitors in transgenic p ig organs prolongs the survival of xenograft in experimental models. Moreov er, the extent of protection from hyperacute rejection is dependent on the level and site of expression of the transgenic molecules and, probably, on the combination of different molecules. In this regard a small animal model to test the efficacy of expression vectors and different human molecules c ould be very advantageous. A murine model developed in our laboratory was c haracterized by measurement of several parameters characteristic of HAR in the livers of control and transgenic mice expressing transgenic human DAF ( CD55) or MCP (CD46) at the end of 2 h of perfusion with human plasma and af ter 1 day. The parameters studied were heamatological values of hepatic fun ctions (GOT and GPT), induction of pro-inflammatory molecules and histopath ological evaluation. Cytokines (IL-1 alpha, IL-1 beta, IL-6) induction and exposure of P-selectin on the endothelial cell surface, was only observed i n control animals after 2 h of perfusion, as an early event. GOT and GPT va lues increase drammatically after 2 h perfusion and 1 day after the treatme nt according to the histopathological observation of liver damage. On the c ontrary, the livers of hDAF or hMCP transgenic mice, under the same treatme nt were significantly protected although the extent of this protection is d ependent on the level of expression of transgenic human molecules.