Future directions in transplantation: xenotransplantation

Xenotransplantation would overcome the worldwide shortage of organs for transplantation. However, xenotransplantation using primate organs is unpracticable, and xenotransplantation between phylogenetically disparate species results in hyperacute rejection. This fulminant form of rejection is mediated by both naturally occurring xeno-antibodies and by direct activation of the alternative pathway of complement. The precise specificities of the xeno-antibodies are incompletely understood and better characterization of these antibodies and their target antigens is needed to allow the development of therapeutic maneuvers, such as immunoadsorption of the relevant antibodies. The direct activation of the alternative pathway of complement by xenogeneic tissue is due, at least in part, to the lack of appropriate (human) membrane bound regulators of complement on the xenogeneic cells. These regulatory molecules, called homologous restriction factors, are species specific, and act to favor inactivation of the complement cascade if the complement is of the same species. Human homologous restriction factors are capable of protecting xenogeneic cells from lysis mediated by human complement. The study of cell-mediated rejection in xenotransplantation has been largely overshadowed by hyperacute rejection. Resolution of the barriers to xenotransplantation will benefit the ever growing number of patients awaiting transplantation.