Antibody-mediated activation of the classical complement pathway in xenograft rejection

Transplant rejection is a multifactorial process involving complex interactions between components of the innate and the acquired immune system. In view of the shortage of donor organs available for transplantation, xenotransplantation of pig organs into man has been considered as a potential solution. However, in comparison to allografts, xenografts are subject to extremely potent rejection processes that are currently incompletely defined. Consequently, an appropriate and safe treatment protocol ensuring long-term graft survival is not yet available. The first barrier that has to be taken for a xenograft is hyperacute rejection, a rapid process induced by the binding of pre-formed antibodies from the host to the graft endothelium, followed by activation of the classical complement pathway. The present review concentrates on the role of antibodies and complement in xenograft rejection as well as on the approaches for treatment that target these components. The first part focuses on porcine xenoantigens that are recognized by human xenoreactive antibodies and the different treatment strategies that aim on interference in antibody binding. The second part of the review deals with complement activation by xenoreactive antibodies, and summarizes the role of complement in the induction of endothelial cell damage and cell activation. Finally, various options that are currently under development for complement inhibition are discussed, with special reference to the specific inhibition of the classical complement pathway by soluble complement inhibitors.