A Perspective on Xenograft Rejection and Accommodation1

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Abstract
There is increasing interest in the potential clinical application of xenotransplantation. This interest derives in part from the need to identify a more abundant source of organs for transplantation and in part from rapid progress in understanding the cellular and molecular events that contribute to xenograft rejection. Recent areas of progress include the characterization of xenoreactive antibodies which would initiate the rejection of porcine organs transplanted into primates. These antibodies consist predominantly of IgM and their binding is characterized by high avidity and surprising uniformity. Xenoreactive antibodies recognize porcine glycoproteins of the integrin family; the determinants residing on N-linked substitutions. The predominant substitution has a terminal alpha Gal residue. Antibody binding initiates activation of complement through the classical pathway triggering a number of effector mechanisms. These mechanisms may include loss of heparan sulfate from endothelial cells mediated by C5a and xenoreactive antibody; a change in endothelial cell shape mediated by C5b-7 or the membrane-attack complex; procoagulant changes mediated by the membrane-attack complex; and neutrophil adhesion mediated by iC3b. If hyperacute rejection is prevented by the depletion of xenoreactive antibody and/or the inhibition of complement, acute vascular rejection may be seen some days later. Acute vascular rejection is characterized by prominent evidence of thrombosis and neutrophil infiltration. The cause of acute vascular rejection is unknown, but may reflect profound alterations in the function of endothelial cells lining blood vessels in the graft. In some cases, when recipients of xenografts are modified by depletion of xenoreactive antibodies, acute vascular rejection does not occur; rather, a process called accommodation allows the xenograft to survive despite the return to the circulation of xenoreactive antibodies and complement. The mechanism for accommodation is not known. New therapeutic strategies including the development of specific immunoabsorbants, identification of preferred donor animals expressing low levels of antigen and the development of transgenic donor animals expressing human complement regulatory proteins are among the strategies which may bring xenotransplantation closer to the clinical arena.