The major problem in the field of cardiac transplantation is the lack of human organs and tissuesfor those who need them. This problem is so severe that by some estimates only 5-15% of theheart transplants needed are carried out; this shortage may worsen as medical advances allowdiseases of aging, such as diabetes and atherosclerosis, to be increasingly prevalent. Oneapproach to overcoming this problem is to use animal organs in lieu of human organs fortransplantation, that is xenotransplantation. However, cardiac xenotransplantation is notpresently feasible because the immune system of the recipient immune reacts severely with thegraft causing vascular diseases such as hyperacute and acute vascular rejection, and possiblychronic rejection. Triggered by the binding of xenoreactive antibodies and the activation ofcomplement, acute vascular rejection destroys organ xenografts over a period of days to weeksand is now the main impediment to clinical application of xenotransplantation. Despite theseverity of this condition, acute vascular rejection is not an invariable outcome of cardiacxenotransplantation. Under some conditions, such as when xenoreactive antibodies aretemporarily depleted, a graft may seemingly acquire resistance to injury by anti-donorantibodies, a condition referred to as accommodation. This application proposes studies that willaddress the problem of acute vascular rejection and test new strategies for understanding andgenerating accommodation. The first objective will be to determine which antigens provokerejection of organs from Gala1-3Gal-deficient pigs. Since rejection of these organs appears alsoto be caused by acute vascular rejection, novel strategies will be tested for abrogating the B cellresponses causing this condition. A second objective will be to induce resistance of cells andorgans to acute vascular rejection, thus determining how accommodation can be more reliablyinduced. New strategies toward this end will be tested. Fulfilling these objectives will yield muchprogress toward the preventing of acute vascular rejection or promoting the occurrence ofaccommodation of cardiac xenografts and allografts.
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