The pathogenesis of hyperacute xenograft rejection

A critical shortage of donor organs has driven many in the transplantation community to consider the use of animals as organ donors for humans, that is, xenotransplantation. While successful xenotransplantation of primate kidneys was achieved 25 years ago, most now advocate use of nonprimates as donors because of the risk of disease transmission and ethical concerns attendant to the use of primates. The major hurdle to xenotransplantation of organs between phylogenetically disparate species is the hyperacute rejection reaction that invariably destroys organ xenografts placed in unmodified recipients. Here we review recent insights concerning the pathogenesis of hyperacute rejection reactions. We focus particular attention on the endothelial cell, which serves not only as the target of xenoreactive antibodies and complement, but also, as a consequence of endothelial cell activation, as an instrument of tissue injury. We discuss a phenomenon called "accommodation" in which an organ graft acquires resistance to humoral-mediated injury.