Mechanisms Underlying Tolerance of Kidney and islet Allotransplants

肾脏和胰岛同种异体移植耐受的潜在机制

基本信息

批准号：
8432087
负责人：
GILLES A BENICHOU
金额：
$ 20.36万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432087
关键词：
Acute Allogenic Animals Antibodies Antigens Autoimmune Diseases B-Lymphocyte Subsets B-Lymphocytes Blood Cells Bone Marrow Cells Bone Marrow Transplantation Cells Chimerism Chronic Clinical Disease Generations Graft Survival Heart Hematopoietic Human Hypersensitivity Immune Immune response Immunologic Factors Immunosuppression In Vitro Inflammatory Inflammatory Response Infusion procedures Instruction Islets of Langerhans Kidney Kidney Transplantation Knowledge Leukocytes Macaca fascicularis Maintenance Mediating Memory Modeling Monkeys Nature Organ Patients Prevention Primates Procedures Protocols documentation Recovery Regulation Regulatory T-Lymphocyte Resistance Series Specificity Stress T cell response T memory cell Testing Time Transplantation allograft rejection allotransplant conditioning design improved in vivo islet isoimmunity kidney allograft nonhuman primate novel strategies programs reconstitution response

项目摘要

Our current mixed chimerism has reliably achieved long-term kidney graft survival exclusively in monkeys (60%) displaying low memory T cell reactivity against their donors prior to transplantation in cynomolgus monkeys (5-7). The presence of regulatory T cells (Tregs) capable of suppressing anti-donor inflammatory responses in vitro was consistently detected in tolerant animals. On the other hand, monkeys displaying high anti-donor memory responsiveness rejected kidney allografts in an acute fashion (6,7). Finally, it is important to note that approximately half of the long-term surviving kidney allografts succumb eventually to chronic rejection (8). These observations stress the need to improve our protocol in order to achieve tolerance to kidney and islet/kidney transplants in 100% of monkeys. Projects 1 and 2 of this program project propose a series of novel strategies designed to induce tolerance to kidney and islet/kidney allografts in monkeys. Successful tolerance induction in both of these studies rely on the basic principles that prevention/suppression of pro-inflammatory alloimmunity combined with enhancement of immune regulation will promote tolerogenesis. Proiect 3 is 1) to investigate the mechanisms by which the in vivo treatments described in Projects 1 and 2 influence the immune response in monkeys transplanted with allogeneic kidneys, islets or islet/kidneys and, 2) elucidate the nature of the cells, soluble factors and immunological mechanisms involved in induction and maintenance of transplant tolerance. This knowledge will help us determine how to select the appropriate donor/recipient combinations and to refine the treatments proposed in Project 1 and 2 in order to reliably achieve tolerance to kidney and islet transplants in primates. To study this, we propose the following Aims: Specific aim 1. Investigate donor hematopoietic mixed chimerism, leukocyte recovery and deleterious alloimmune T cell responses in transplanted monkeys Specific aim 2. Investigate regulatory T cell responses associated with transplant tolerance Specific aim 3. Investigate B cell responses and their contribution to rejection and tolerance Understanding the mechanisms by which tolerance is induced and maintained in our primate transplant model should significantly expand the successful application of tolerance protocols in clinical transplantation and for the treatment of immune-mediated diseases requiring tolerogenesis of harmful memory T cells in patients such as autoimmune disorders and allergies.

我们目前的混合嵌合体仅在猴子 (60%) 中可靠地实现了肾移植的长期存活，在移植到食蟹猴 (5-7) 之前，这些猴子对其供体表现出低记忆 T 细胞反应性。在耐受动物中始终检测到能够在体外抑制抗供体炎症反应的调节性 T 细胞 (Treg) 的存在。另一方面，猴子表现得很高抗供体记忆反应以急性方式排斥同种异体肾移植物 (6,7)。最后，值得注意的是，大约一半的长期存活的同种异体肾移植物最终死于慢性排斥反应 (8)。这些观察结果强调需要改进我们的方案，以实现 100% 猴子对肾脏和胰岛/肾脏移植的耐受性。该计划项目的项目 1 和项目 2 提出了一系列新颖的策略，旨在诱导猴子对肾脏和胰岛/肾脏同种异体移植物的耐受性。这两项研究中成功的耐受诱导依赖于预防/抑制促炎同种免疫与免疫调节的增强将促进耐受性的发生。项目 3 是 1) 研究项目 1 和 2 中描述的体内治疗影响移植同种异体肾脏、胰岛或胰岛/肾脏的猴子的免疫反应的机制，2) 阐明细胞、可溶性因子的性质以及涉及诱导和维持移植耐受的免疫机制。这些知识将帮助我们确定如何选择合适的供体/受体组合，并完善项目 1 和 2 中提出的治疗方法，以便可靠地实现灵长类动物对肾脏和胰岛移植的耐受性。为了研究这个问题，我们提出以下目标：具体目标 1. 研究移植猴中供体造血混合嵌合、白细胞恢复和有害同种免疫 T 细胞反应具体目标 2. 研究与移植耐受相关的调节性 T 细胞反应具体目标 3. 研究 B 细胞反应及其对排斥和耐受的贡献了解在我们的灵长类移植模型中诱导和维持耐受性的机制将显着扩大耐受方案在临床移植中的成功应用，以及治疗需要患者体内有害记忆 T 细胞耐受的免疫介导疾病，例如自身免疫性疾病和免疫性疾病。过敏。