Mechanisms Underlying Tolerance of Kidney and islet Allotransplants

我们目前的混合嵌合体仅在猴中可靠地实现了长期肾移植存活（60%），在移植到食蟹猴中之前显示出对其供体的低记忆T细胞反应性（5-7）。在耐受性动物中一致检测到能够抑制体外抗供体炎症反应的调节性T细胞（TCFs）的存在。另一方面，猴子表现出高 抗供体记忆反应性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%的猴子中实现对肾脏和胰岛/肾脏移植的耐受性。 该项目的项目1和项目2提出了一系列旨在诱导猴子对肾脏和胰岛/肾脏同种异体移植物耐受的新策略。在这两项研究中成功的耐受诱导依赖于预防/抑制促炎性同种异体免疫与免疫抑制相结合的基本原则。 增强免疫调节将促进耐受性发生。 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、胰岛或胰岛/肾的猴的免疫应答的机制，2）阐明细胞的性质、可溶性因子和参与诱导和维持移植耐受性的免疫机制。这些知识将帮助我们确定如何选择合适的 本研究的目的是确定供体/受体组合，并改进项目1和2中提出的治疗方法，以可靠地实现对灵长类动物肾脏和胰岛移植的耐受性。为了研究这个问题，我们提出以下目标： 具体目标1.研究移植猴中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 具体目标2。研究与移植耐受相关的调节性T细胞应答 具体目标3。研究B细胞反应及其对排斥和耐受的作用 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和治疗免疫介导的疾病中的成功应用，这些疾病需要在患者中对有害的记忆T细胞进行耐受性发生，如自身免疫性疾病和过敏。

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.