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Mechanisms Underlying Delayed Transplant Tolerance

延迟移植耐受的潜在机制

基本信息

批准号：
8990982
负责人：
GILLES A BENICHOU
金额：
$ 21.38万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2016-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Transplant tolerance, defined as indefinite allograft survival in the absence of immunosuppression and chronic rejection, has been achieved in monkeys and patients via infusion of recipients with donor bone marrow cells given in conjunction with kidney transplantation from the same living donor. Tolerance depends upon transient mixed hematopoietic chimerism and the activation of regulatory T cell. This procedure requires conditioning of recipients with donor bone marrow 6 days prior to transplantation and thus cannot be applied to recipients of organs from deceased donor. Recently, we have shown that tolerance can also be achieved via infusion of donor bone marrow cells performed several months after transplantation of monkeys with an allogeneic kidney whose survival had been maintained via conventional immunosuppression. However, this procedure called "the delayed protocol" is unsuccessful in over 50% of monkeys, which become sensitized to their donor owing to the generation and reactivation of donor-specific memory T cells after kidney transplantation (8-12). The limited success stresses the need to design novel strategies to harness alloreactive memory T cells while promoting the activation of regulatory T cells prior to or after transplantation, thereby facilitating tolerance. Recently, we have developed a mouse delayed mixed chimerism tolerance model, which recapitulates the features observed in monkeys and patients. These results correlate with previous observations in primates showing 1) the tolerogenic properties of delayed transient mixed chimerism, 2) the deleterious effects of donor-specific memory T cells, and 3) the requirement for regulatory B cells (Bregs) in allograft tolerance. Altogether, this suggests that treatments designed to stimulate Bregs or adoptive transfer of Bregs may be used to prevent or suppress donor-specific memory T cell responses and promote transplant tolerance induction in naive and sensitized transplant recipients. In this study, we propose the following specific aims: Specific Aim 1: To investigate the ability of regulatory B cells to inhibit the generation and reactivation of alloreactive memory T cells and to restore tolerance in naïve and sensitized mice. Specific Aim 2: To investigate the mechanisms by which B cells control transplant tolerance induced via delayed mixed chimerism. If successful, these studies will provide insight into the mechanisms underlying tolerance achieved via delayed mixed chimerism and set the path for the design of B-cell-based strategies capable of harnessing alloreactive memory T cells, which is essential to the successful translation of our tolerance protocol in clinical settings.

描述（由申请人提供）：移植耐受性，定义为在没有免疫抑制和慢性排斥反应的情况下无限期的同种异体移植物存活，已在猴和患者中通过输注供体骨髓细胞与来自同一活体供体的肾移植联合使用实现。免疫耐受依赖于短暂的混合造血嵌合体和调节性T细胞的激活。该程序需要在移植前6天用供体骨髓对受体进行预处理，因此不能应用于来自死亡供体的器官的受体。最近，我们已经表明，也可以通过输注供体骨髓细胞移植后几个月的同种异体肾，其生存已通过传统的免疫抑制维持猴子实现的耐受性。然而，这种被称为“延迟方案”的程序在超过50%的猴子中是不成功的，由于肾移植后供体特异性记忆T细胞的产生和再活化，猴子对其供体变得敏感（8-12）。有限的成功强调需要设计新的策略来利用同种异体反应性记忆T细胞，同时促进移植前或移植后调节性T细胞的激活，从而促进耐受。最近，我们开发了一种小鼠延迟混合嵌合耐受模型，该模型概括了在猴子和患者中观察到的特征。这些结果与先前在灵长类动物中观察到的结果相关，显示1）延迟性瞬时混合嵌合体的致耐受性特性，2）供体特异性记忆T细胞的有害作用，和3）同种异体移植物耐受性中对调节性B细胞（BCRs）的需求。总而言之，这表明，设计用于刺激贝伐单抗或贝伐单抗的过继转移的治疗可用于预防或抑制供体特异性记忆T细胞应答，并促进幼稚和致敏移植受者的移植耐受诱导。在这项研究中，我们提出了以下具体目标：具体目标1：研究调节性B细胞抑制同种异体反应性记忆T细胞的产生和再活化的能力，在未处理和致敏小鼠中恢复耐受性。具体目标2：研究B细胞控制通过延迟混合嵌合体诱导的移植耐受的机制。如果成功的话，这些研究将深入了解通过延迟混合嵌合体实现耐受的潜在机制，并为设计能够利用同种异体反应性记忆T细胞的基于B细胞的策略奠定基础，这对我们在临床环境中成功翻译耐受方案至关重要。