Beyond hyperacute rejection: strategies for development of pig-->primate xenotransplantation

The status of xenotransplantation of pig organs is considered in light of the current problems and their potential solutions. This emphasis on a very recent perspective necessarily omits earlier aspects that are well described in historical reviews. However, the field is now witnessing the products of intensive studies using molecular biology and other approaches, including the testing, and establishment as baseline for all future applications, of pigs transgenic for human regulators of complement activation (RCA). Use of such pigs as organ donors now avoids hyperacute rejection of cardiac or renal xenografts by untreated primate recipients, but grafts are rejected by five days post-transplantation. Addition of immunosuppression with cyclophosphamide and steroids has led to survival of a single such cardiac xenograft for 63 days, though the protocol used is not clinically applicable and organ function was not rigorously assessed. Consideration of the role of various effector mechanisms contributing to rejection of organ xenografts indicates that additional strategies to genetically modify the donor may facilitate organ survival post-transplantation with far less intensive, and toxic, immunosuppression.