Inducing Xenotolerance via Chimeric Thymus

ABSTRACT: Inducing Xenotolerance via Chimeric Thymus Lack of sufficient organ donors currently limits the availability of life-saving organ transplantations in humans. Transplantation of organs from genetically modified pigs has been proposed as a way of overcoming this limitation, but success has thus far been limited by relatively short survival of pig xenografts in humans. Inducing tolerance that provides specific unresponsiveness to donor pig tissues while maintaining otherwise normal immune function could make xenotransplantation feasible for long-term, definitive organ replacement. Tolerance to self-antigens normally develops as the result of positive and negative selection of T cell precursors as they develop within the thymus. Our pivotal prior work established that human allogeneic cultured thymus tissue implantation (CTTI) into athymic human recipients results in robust immunity, with a functional donor-recipient chimeric thymus that generates T cells that are tolerant to both recipient and donor antigens. Previous studies by others have shown that porcine thymus can interact with human cells and promote some degree of xenotolerance in animal models. However, those models generally have required fetal thymus tissue and their human cells have suboptimal immune function. Here, we will leverage our unparalleled expertise as developers of CTTI and its success in inducing robust immunity and donor-specific tolerance in athymic humans to provide critical proof of concept that xenogeneic CTTI can generate xenotolerance in human T cells. The specific aim of this proposal is to determine the ability of cultured postnatal pig thymus slices to attract human thymocyte precursors and antigen presenting cells (APCs) and to support positive and negative selection in vivo in humanized immunodeficient mouse models. These studies will contribute to the understanding of factors important in normal thymus function, facilitate optimization and engineering of cultured thymus slices to enhance tolerance induction, and advance development of strategies to induce tolerance toward allogeneic and xenogeneic solid organs.