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

• 批准号: 8725787
• 负责人: GILLES A BENICHOU
• 金额: $ 21.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/8725787
• 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; Hematopoietic; 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; Patients; Prevention; Primates; 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

PROJECT SUMMARY (See instructions): 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. Project 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.

项目摘要（请参阅说明）： 我们目前的混合嵌合体可靠地在猴子（60％）中可靠地实现了长期的肾脏移植物存活率（60％），在cynomolgus猴子移植之前，对其供体显示低记忆T细胞反应性（5-7）。在耐受动物中始终检测到能够抑制抗抑制性炎症反应的调节性T细胞（Tregs）的存在。另一方面，表现出较高的抗抑制记忆反应能力的猴子以急性的方式拒绝了肾脏同种异体移植物（6,7）。最后，重要的是要注意，大约一半的长期存活肾脏同种异体移植最终屈服于慢性拒绝（8）。这些观察结果强调需要改善我们的方案，以便在100％的猴子中实现对肾脏和胰岛/肾脏移植的耐受性。 该计划项目的项目1和2提出了一系列新型策略，旨在诱导猴子中对肾脏和胰岛/肾脏同种异体移植的耐受性。这两项研究中的成功耐受性诱导均取决于预防/抑制促炎性同种免疫性以及增强免疫调节的基本原理，将促进耐受生成。 项目3是1）研究项目1和2中描述的体内处理的机制，影响了用同种异体肾脏，胰岛或胰岛/肾脏移植的猴子中的免疫反应，以及2）阐明了细胞，可溶性因子和免疫机制的性质，涉及移植耐受性的诱导和维持。这些知识将有助于我们确定如何选择合适的供体/接受者组合，并完善项目1和2中提出的治疗方法，以可靠地实现灵长类动物中对肾脏和胰岛移植的容忍度。为了研究这一点，我们提出以下目的： 具体目的1。研究移植的猴子中的供体造血混合嵌合，白细胞恢复和有害的同种免疫T细胞反应 具体目标2。研究与移植耐受性相关的调节性T细胞反应 特定目的3。研究B细胞反应及其对排斥和耐受性的贡献 了解在我们的灵长类动物移植模型中诱导和维持耐受性的机制，应显着扩大耐受性方案在临床移植中的成功应用，以及治疗需要在自身免疫性疾病和过敏的患者中对有害记忆T细胞的免疫介导疾病的治疗。