Induction of Cytoprotection to Avert Xenograft Rejection

描述(申请人提供)：异种移植，如将猪的器官移植到灵长类动物身上，由于人体器官供应不足，引起了极大的兴趣。然而，为了克服异种移植成功的强大免疫学障碍，有必要修改供体器官，使其免受急性血管排斥(AVR)的影响。一种方法是用已知的刺激保护的药物在捐献器官(如心脏)中诱导保护。要研究的假设是保护性细胞因子IL-4可以用于准备移植的异种移植物，使器官不被AVR排斥。将研究IL-4诱导的对内皮细胞的激活、坏死和凋亡的保护作用。将研究IL-4诱导的保护机制，并确定Akt下游的候选效应分子。然后，小鼠的心脏将经过基因改造，表达IL-4，并移植到大鼠体内。如果这一假设在这个模型中被证明是正确的，那么将转基因心脏移植到非人类灵长类动物中将是合理的。将细胞因子诱导的保护与其他形式的供体修饰相结合，将大大有助于临床异种移植的成功。

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.