Induction of Cytoprotection to Avert Xenograft Rejection

描述（由申请人提供）：异种移植，例如将猪的器官移植到灵长类动物，由于人体器官供应不足而引起极大兴趣。然而，为了克服现有的强大的免疫屏障，成功的异种移植，有必要修改供体器官，使其免受急性血管排斥反应（AVR）。一种方法是用已知的刺激保护作用的试剂在供体器官（如心脏）中诱导保护作用。待研究的假设是保护性细胞因子IL-4可用于制备用于移植的异种移植物，使得器官不被AVR排斥。将研究IL-4诱导的保护内皮细胞免于活化、坏死和凋亡。将研究IL-4诱导的保护机制，并鉴定Akt下游的候选效应分子。然后将小鼠心脏进行基因修饰以表达IL-4并移植到大鼠体内。如果这一假设被证明是正确的，那么将转基因心脏移植到非人类灵长类动物身上将是合理的。联合应用精氨酸诱导的保护作用和其他形式的供体修饰，将显著促进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.