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：
7609171
负责人：
KAZUHIKO YAMADA
金额：
$ 35.48万
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 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7609171
关键词：
Allogenic Animals Antibodies Antigens B-Lymphocytes Biological Assay Biopsy Blood Coagulation Disorders Cell physiology Cells Cellular Immunity Class 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 Purpose Role Schedule Series Skin Transplantation Skin graft Specificity Steroids Sus scrofa T-Cell Receptor-Rearrangement Excision DNA Circles T-Lymphocyte Testing Therapeutic immunosuppression Thymic Tissue Thymus Gland Time Transplantation Transplantation Tolerance Treatment Protocols Withdrawal Xenograft procedure Yang base cobra venom factor day 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 的总体目标是诱导猪对狒狒异种动物的持久耐受性通过血管化胸腺移植物的移植来屏障。为此，我们将：1）优化我们的免疫抑制药物治疗方案：我们之前已经证明，血管化胸腺移植物支持胸腺生成并诱导完全不匹配的同种异体的移植耐受障碍。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治疗方案； 2）判断是否嫁接胸腺可以诱导对来自基因相同的近交供体动物的肾异种移植物的耐受性给胸腺捐赠者。如果成功，该策略将扩展到同时胸腺+ 肾异种移植； 3）阐明供体胸腺诱导耐受的机制，使用体外测定并关注跨越该物种屏障的耐受特异性。这些研究将与该 PPG 中的其他项目高度互动。因此，最佳治疗如有必要，将根据猪到灵长类小鼠模型的结果修改治疗方案 Sykes 及其同事在项目 3 中研究了通过胸腺移植产生的耐受性。如果最终抗体介导的排斥反应不能通过胸腺有效预防移植后，我们将尝试通过将胸腺移植与造血移植，正在项目2中研究。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。我们共同希望这些研究将为胸腺移植在诱导中的潜在作用提供新的见解移植耐受性。