CHIMERISM AND TRANSPLANTATION TOLERANCE

器官移植是治疗癌症的一种重要形式。 治疗晚期肾脏、肝脏和心脏疾病。 不幸的是， 目前的临床实践依赖于有效的、非特异性的 免疫抑制药物既不完全成功， 防止排异或免于并发症。为了发展 更具体和有效的治疗方法，我们必须改善 我们对同种异体移植排斥反应过程的理解， 耐受诱导策略。该研究将开发 并评估非清髓性方案诱导无限期同种异体移植 存活和耐受性，从而促进合理的 将这种干预应用于临床移植。 我们的核心假设是捐赠者的骨髓 输血和CTLA 4-IG治疗将提供临床相关的 意味着无限期延长同种异体移植物存活， 移植耐受我们建议在 小鼠系统，因为它既提供了血管化的心脏同种异体移植物， 模型，其中完善这种治疗方案和独特的细胞和 分析免疫机制的分子工具。具体到 这个模型，我们将：（1）定义最佳协议的诱导 使用CTLA 4 - 1和CTLA 4 - 2的组合的供体特异性移植耐受性 IG和供体骨髓移植（BMT）;（2）使用分子， 免疫组织学和流式细胞术技术来表征 CTLA 4-IG/BMT造血嵌合体的形成及性质 移植受者;（3）确定造血嵌合体在 CTLA 4-IG/BMT诱导的移植耐受：（4）检测CTLA 4-Ig/BMT诱导的移植耐受的发生率。 延长同种异体移植物存活时间所需的关键细胞群 使用缺乏或富集的骨髓移植的存活率 对于特定的细胞谱系;（5）测试施用 建立嵌合体的关键细胞群， 移植耐受性;（6）分析移植耐受性的特异性改变。 与CTLA 4-IG/BMT相关的受体T细胞群 诱导耐受性的发展及机理分析 CTLA 4-IG/BMT诱导小鼠免疫耐受的最佳方案 将使这些知识应用于大型动物移植模型 为了测试CTLA 4-IG/BMT在移植前延长同种异体移植物存活的能力， 应用于临床移植。

Transplantation of organs is an important form of therapy for the treatment of end-stage kidney, liver and heart disease. Unfortunately, current clinical practice relies on potent, non-specific immunosuppressive drugs which are neither totally successful in preventing rejection nor free from complications. In order to develop more specific and effective therapies it is imperative that we improve our understanding of the process of allograft rejection and develop novel strategies for tolerance induction. The proposed research will develop and assess a non-myeloablative protocol to induce indefinite allograft survival and tolerance in a murine model and thus facilitate the rational application of such intervention to clinical transplantation. Our central hypothesis is that the combination of donor bone marrow transfusion and CTLA4-Ig treatment will provide a clinically relevant means to prolong allograft survival indefinitely and induce transplantation tolerance. We propose to test this hypothesis in the murine system because it provides both a vascularized cardiac allograft model in which to refine this treatment protocol and unique cellular and molecular tools to analyze the immunologic mechanisms. Specifically, in this model we will: (1) define the optimal protocol for the induction of donor specific transplantation tolerance using the combination of CTLA4- Ig and donor bone marrow transplant (BMT); (2) use molecular, immunohistological, and flow cytometric techniques to characterize the development and nature of hematopoietic chimerism in CTLA4-Ig/BMT transplant recipients; (3) define the role of hematopoietic chimerism in transplantation tolerance induced by CTLA4-Ig/BMT: (4) determine the critical cell population required for the prolongation of allograft survival using bone marrow transplants either deficient in or enriched for specific cell lineages; (5) test the efficacy of administering the critical cell population for the establishment of chimerism and transplantation tolerance; (6) analyze the specific alterations in the recipient T cell population which are associated with CTLA4-Ig/BMT induced tolerance. The development and mechanistic analysis of the optimal CTLA4-Ig/BMT protocol for tolerance induction in the murine model will allow this knowledge to be applied large animal transplant models to test the ability of CTLA4-Ig/BMT to prolong allograft survival prior to application to clinical transplantation.