The inadequate supply of human organs has created a strong interest in the use of non- primate organs for clinical transplantation, but vigorous immune reactions prevent their current use in humans. Recent genetic approaches have generated porcine organs that are significantly resistant to complement-mediated hyperacute rejection. Nonetheless, they elicit a significant immune response in primates or humans and are ultimately rejected in a process labeled delayed xenograft rejection (DXR) or acute vascular rejection (AVR). DXR/AVR is predominantly mediated by xenoreactive antibodies (XAbs) that bind to and cause endothelial cell activation in the xenograft. Remarkably, the natural and the elicited XAbs that mediate the rejection of porcine grafts in human and Old World monkeys are directed predominantly against a single carbohydrate epitope, galactose-alpha1,3-galactose (alphaGal). Opportunities to study the immunological basis of anti-alphaGal antibody production in a xenotransplantation setting have been limited, historically, to humans and Old World monkeys, since all other mammals do not make anti-alphaGal Abs. However, the recent generation of alpha1,3galactosyltransferase knockout (GT-KO) mice, which do not express the alphaGal epitope and can spontaneously make anti-alphaGal Abs, has provided a new model system for a reductionist approach to studying alphaGal-mediated xenotransplant rejection. Using these mice, the investigators propose (1) to use in vivo and ex vivo approaches to define the B cell subsets producing natural and elicited anti-alphaGal Ab responses; (2) to define the role of cytokines in regulating anti-alphaGal Ab responses and xenograft rejection; and (3) to control anti-alphaGal Ab responses and xenograft rejection using pharmacological and biological immunosuppressants, then use in vivo and ex vivo approaches to define the immunological basis for the successful control. The investigators propose that these studies will lead to an improved understanding of the immune regulation of anti- alphaGal responses and of xenograft rejection, and ultimately to the development of new genetic and/or immunosuppressive strategies that allow xenografts to survive and function in humans.
