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

使用 GAIT-KO 血管化胸腺移植来诱导…………

基本信息

批准号：
7790538
负责人：
KAZUHIKO YAMADA
金额：
$ 36.33万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-15 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7790538
关键词：
Allogenic Animals Antibodies Antigens B-Lymphocytes Biological Assay Biopsy Blood Coagulation Disorders Cell physiology Cells Cellular Immunity Coculture Techniques Data Detection Effectiveness Engraftment FK506 Family suidae Gait Galactosyltransferases Generations Genes Goals Haplotypes Health Hematopoietic Immune response Immunity Immunocompetence Immunosuppression Immunosuppressive Agents In Vitro Kidney Knock-out Laboratories Life Lobe Mediating Membrane Glycoproteins Miniature Swine Modeling Monitor Mus Organ Organ Transplantation Papio Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Primates Principal Investigator Production Progress Reports Protocols documentation Role Schedule Series Skin Transplantation Skin graft Specificity Steroids T-Cell Receptor-Rearrangement Excision DNA Circles T-Lymphocyte Testing Thymic Tissue Thymus Gland Time Transplantation Transplantation Tolerance Treatment Protocols Withdrawal Xenograft procedure Yang base cobra venom factor design in vitro Assay insight kidney xenograft knockout animal mouse model mycophenolate mofetil prevent programs research study response sugar thymus transplantation

项目摘要

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.

项目1的总体目标是在猪到狒狒的异种中诱导持久的耐受性通过移植带血管的胸腺形成屏障。为此，我们将：1)优化我们的免疫抑制药物方案：我们之前已经证明了血管胸腺移植物支持胸腺生成并诱导完全不相合的同种异体移植耐受障碍。在这个异种模型中，我们将尝试优化免疫调节治疗实现持久胸腺植入所需的养生法；2)确定植入的胸腺胸腺可以诱导对来自基因相同近亲交配供体动物的异种肾移植的耐受给胸腺捐赠者。如果成功，该策略将扩展到同时胸腺加 3)阐明供者胸腺诱导耐受的机制。使用体外试验，并重点研究跨越该物种屏障的耐受性的特异性。这些研究将与PPG中的其他项目高度互动。因此，最佳的治疗方法是如果有必要，将根据猪到灵长类动物的小鼠模型的结果来修改方案赛克斯和他的同事在项目3中正在研究胸腺移植的耐受性。如果最终抗体介导的排斥反应不能通过胸腺有效地预防移植，我们将尝试通过联合胸腺移植和造血移植，正在项目2中研究。我们还将与项目5合作观察移植后凝血功能紊乱的机制。一起，我们希望这些研究将为胸腺移植在诱导胸腺移植中的潜在作用提供新的见解移植耐受。