Xenogeneic Natural Antibody Targets-Structure/Function

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DESCRIPTION (provided by applicant): The major problem in the field of transplantation is the lack of human organs and tissues for those who need them. This problem is so severe that by some estimates only 5-15 percent of the organ transplants needed is carried out. One approach to overcoming this problem is to use animal organs in lieu of human organs for transplantation, that is xenotransplantation. While xenotransplantation could in principle solve the problem of the shortage of organs, it is not presently feasible because the immune system of the recipient reacts severely with the graft. The first manifestation of this reaction is hyperacute rejection. Triggered by the binding of xenoreactive antibodies and the activation of complement, hyperacute rejection can now be overcome by various means including the use of pigs expressing human complement regulatory proteins as the source of xenografts. When hyperacute rejection is averted, a xenograft is subject to acute vascular rejection. Acute vascular rejection destroys organ xenografts over a period of days to weeks. It appears to be caused by antibodies in the recipient, which bind to blood vessels in the graft causing activation of endothelial cells and tissue injury that ensues. Fortunately, acute vascular rejection is not an invariable outcome of organ xenografts. Under some conditions, such as when xenoreactive antibodies are temporarily depleted, a graft may seemingly acquire resistance to injury by anti-donor antibodies, a condition referred to as accommodation. This application proposes studies that will elucidate the nature of the xenoreactive antibodies that cause acute vascular rejection of cardiac xenografts and determine how antibodies or other factors reacting with a graft may induce accommodation. Studies will be conducted in a model system in which porcine hearts are transplanted heterotopically into baboons. The antibodies produced by the baboons in response to the porcine organs will be studied at the time that acute vascular rejection or accommodation occurs. The specificity of those antibodies, number of antigens and frequency in pigs will be determined and the mechanisms by which those antibodies or other factors induce changes in endothelial cells will be ascertained. These experiments will provide information critical to the devising of new strategies for preventing acute vascular rejection or promoting the occurrence of accommodation of cardiac xenografts.