Mechanisms Underlying Delayed Transplant Tolerance

 描述(由申请人提供)：移植耐受，定义为在没有免疫抑制和慢性排斥的情况下，同种异体移植物无限期存活，已在猴子和患者身上实现，方法是将供者的骨髓细胞与来自同一活体供者的肾移植一起输入受者。耐受性取决于短暂的混合造血细胞嵌合体和调节性T细胞的激活。这一程序需要在移植前6天用供者骨髓对受者进行调理，因此不适用于接受已故供者器官的受者。最近，我们已经证明，通过输注供体骨髓细胞也可以实现耐受，这些供体骨髓细胞是在猴子移植后几个月进行的，其存活是通过传统的免疫抑制维持的。然而，这种被称为“延迟方案”的程序在超过50%的猴子身上并不成功，因为肾移植后供者特有的记忆T细胞的产生和重新激活使猴子对供者变得敏感(8-12)。有限的成功强调了需要设计新的策略来利用同种异体反应性T细胞，同时促进移植前后调节性T细胞的激活，从而促进耐受性。最近，我们开发了一种小鼠延迟混合嵌合体耐受模型，该模型概括了在猴子和患者身上观察到的特征。这些结果与以前在灵长类动物中观察到的结果相关联，表明了1)延迟瞬时混合嵌合体的耐受特性，2)供者特异性记忆T细胞的有害效应，以及3)同种异体移植耐受中对调节性B细胞(Bregs)的要求。总之，这表明旨在刺激Bregs或Bregs过继转移的治疗可以用于预防或抑制供者特异性记忆T细胞反应，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，我们提出了以下特定目标：特定目标1：研究调节性B细胞抑制同种异体反应性记忆T细胞的生成和再激活的能力，并 恢复幼稚和致敏小鼠的耐受性。特异性目的2：探讨B细胞控制延迟混合嵌合体诱导的移植耐受的机制。如果成功，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，并为设计能够利用异体反应性记忆T细胞的基于B细胞的策略铺平道路，这对于我们的耐受方案在临床环境中的成功翻译至关重要。

 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.