Use of GAIT-KO Vascularized Thymic Transplantation for the Induction of..........

项目1的总体目标是诱导猪与狒狒异种之间的持久耐受性 通过移植血管化胸腺移植物的屏障。为此，我们将：1）优化 我们的免疫抑制药物方案：我们以前已经证明， 移植物支持胸腺生成并诱导完全不匹配的同种异体移植耐受 隔栏.在这个异种模型中，我们将尝试优化免疫调节治疗 方案，以实现持久的胸腺移植; 2）确定是否植入 胸腺可以诱导对来自遗传上相同的近交系供体动物的异种肾移植物的耐受性 胸腺捐赠者如果成功，该策略将扩展到同步胸腺加 异种肾移植; 3）阐明供体胸腺诱导耐受的机制， 使用体外分析，并专注于跨越该物种屏障的耐受性的特异性。这些 研究将与本项目规划中的其他项目高度互动。因此，最佳治疗 如有必要，将根据猪到灵长类动物的小鼠模型的结果修改方案 Sykes及其同事在项目3中研究了通过胸腺移植的耐受性。 如果最终的抗体介导的排斥反应不能通过胸腺 移植后，我们将尝试通过结合胸腺移植和 造血干细胞移植，正在研究项目2。我们还将与项目5合作， 观察到的任何移植后凝血障碍的机制。我们一起希望这些 这些研究将为胸腺移植在诱导免疫应答中的潜在作用提供新的见解。 移植耐受

The overall objective of Project 1 is to induce durable tolerance across a pig-to-baboon xenogeneic barrier through transplantation of vascularized thymic grafts. For this purpose, we will: 1) optimize our immunosuppressive drug regimen: We have demonstrated previously that vascularized thymic grafts support thymopoiesis and induce transplant tolerance across fully mismatched allogeneic barriers. In this xenogeneic model, we will attempt to optimize the immunomodulatory treatment regimen required to achieve durable thymus engraftment; 2) determine whether the engrafted thymus can induce tolerance to a kidney xenograftfrom an inbred donor animal genetically identical to the thymus donor. If successful, the strategy will be extended to simultaneous thymus plus kidney xenotransplantation; and 3) elucidate the mechanism of donor thymus-induced tolerance, using in vitro assays and focusing on the specificity of tolerance across this species barrier. These studies will be highly interactive with other projects in this PPG. Thus, the optimal treatment regimen will be modified, if necessary, on the basis of results from a mouse model of pig-to-primate tolerance through thymus transplantation being investigated by Sykes and colleagues in Project 3. If eventual antibody-mediated rejection cannot be effectively prevented through thymic transplantation, we will attempt to induce B-cell tolerance by combining thymic transplantation with hematopoietic transplantation, being studied in Project 2. We will also collaborate with Project 5 on the mechanism of any post-transplant coagulation disorders observed. Together, we hope these studies will provide new insights into the potential role of thymic transplantation in the induction of transplantation tolerance.