Induction of Cytoprotection to Avert Xenograft Rejection

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DESCRIPTION (provided by applicant): Xenotransplantation, such as the transplantation of an organ from a pig to a primate, is of great interest because of the insufficient supply of human organs. However, to overcome the existing strong immunologic barriers to successful xenotransplantation, it is necessary to modify the donor organ such that it becomes protected from acute vascular rejection (AVR). One approach is inducing protection in donor organs, such as the heart, with agents that are known to stimulate protection. The hypothesis to be investigated is that the protective cytokine IL-4 can be used to prepare a xenograft for transplantation, such that the organ is not rejected by AVR. IL-4-induced protection of endothelial cells from activation, necrosis, and apoptosis will be investigated. The mechanisms of IL-4-induced protection will be investigated, and candidate effector molecules downstream of Akt identified. A mouse heart will then be genetically modified to express IL-4 and transplanted into a rat. If the hypothesis is proven correct with this model, transplanting genetically modified hearts into non-human primates will be justified. Combining cytokine-induced protection with other forms of donor modification should significantly contribute to successful clinical xenotransplantation.