Mechanisms Underlying Tolerance of Kidney and islet Allotransplants

项目总结(见说明)： 我们目前的混合嵌合体已经可靠地实现了仅在猴子(60%)身上移植肾的长期存活，在食蟹猴(5-7)移植前对供者表现出低记忆T细胞反应性。在耐受性动物中，一直存在能够抑制体外抗供体炎症反应的调节性T细胞(Tregs)。另一方面，表现出高抗供者记忆反应性的猴子以一种急性的方式排斥同种异体肾移植(6，7)。最后，值得注意的是，长期存活的同种异体肾移植约有一半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，以便在100%的猴子身上实现对肾脏和胰岛/肾脏移植的耐受性。 该计划项目的项目1和2提出了一系列新的策略，旨在诱导猴子对肾脏和胰岛/肾移植的耐受性。在这两项研究中，成功的耐受诱导都依赖于这样一个基本原则，即预防/抑制促炎性同种免疫结合加强免疫调节将促进耐受的发生。 项目3是1)研究项目1和2中描述的体内治疗对移植异基因肾脏、胰岛或胰岛/肾脏的猴子免疫反应的影响机制，2)阐明诱导和维持移植耐受所涉及的细胞的性质、可溶性因素和免疫学机制。这些知识将帮助我们确定如何选择合适的供体/受体组合，并改进项目1和2中提出的治疗方法，以便可靠地实现对灵长类动物肾脏和胰岛移植的耐受性。为了研究这一点，我们提出了以下目标： 具体目的1.研究移植猴的供者造血混合嵌合体、白细胞恢复和有害的同种免疫T细胞反应 特定目标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细胞反应及其在排斥和耐受中的作用 了解在我们的灵长类移植模型中诱导和维持耐受的机制将大大扩展耐受方案在临床移植和治疗免疫介导的疾病中的成功应用，这些疾病需要患者对有害记忆T细胞的耐受产生，如自身免疫性疾病和过敏。

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.