Complement activation, its consequences, and blockade by gene transfer

Abstract

The success of xenotransplanting vascularized pig organs into humans is limited owing to the immediate immune reaction, termed hyperacute rejection (HAR). This reaction is primarily mediated by naturally occurring xenoreactive antibodies binding to the graft and activating the complement system, resulting in organ dysfunction. Pig membrane-bound complement regulatory proteins efficiently control autologous complement only and are unable to protect against human complement-mediated damage. One line of current research to overcome HAR of pig organs involves the expression of human complement regulatory proteins by pig cells. In vitro data have demonstrated that pig endothelial cells expressing human regulators of complement activation (RCAs) are resistant to human complement-mediated attack, which has led to the successful production of pigs transgenic for human RCAs. Ex vivo perfusion studies using fresh human blood with organs from these animals has shown an improvement in graft function and survival through expression of human RCAs compared to that of nontransgenic pig organs. Similar results have been observed in primate models, where expression of human RCA proteins on the pig donor organ has resulted in protection against HAR and prolongation of graft survival. The initial complement-mediated immunologic barrier of HAR has been overcome through this genetic incorporation of human RCAs into pigs, and it is now possible to study the subsequent mechanisms of xenograft rejection in the pig-to-human combination.