B Cells in Transplantation Tolerance

在许多啮齿动物模型中可以实现对同种异体移植物的耐受，并且在许多非人灵长类动物模型中已经报道了移植物的长期存活。稳定的移植物接受的一致特征是控制同种抗体产生;相反，增加的同种抗体滴度的出现预示着 移植物排斥，已经提出了两种不同的解释来解释这些观察结果-第一，同种异体反应性B细胞和同种异体抗体的活化仅仅是同种异体反应性T细胞活化的标志物，并且T细胞是同种异体移植物损失的唯一原因;第二，同种异体反应性B细胞和同种异体抗体有助于移植物排斥;通过与同种异体反应性T细胞或其它效应细胞协同作用而直接或间接地产生。由于B细胞和同种异体抗体的充分表征的致病特性，我们支持第二种解释，并假设除了T细胞外，同种异体反应性B细胞的控制是稳定耐受的核心。 自身免疫性疾病和移植排斥，最初认为主要是T细胞介导的病理，提示B细胞在这些临床环境中的重要作用。同种异体反应性T细胞的命运已经在各种移植耐受模型中被广泛定义，但是实际上没有关于同种异体反应性B细胞命运的信息，我们通过开发一种新的实验模型来可视化同种异体反应性B细胞的命运，从而解决了这种差异。 移植耐受性与成熟同种异体反应性B细胞的缺失和过渡/未成熟同种异体反应性B细胞的保留/富集有关。这些观察结果与最近报道的在非人灵长类动物中改变的B细胞亚群和耐受性之间的相关性以及在自发耐受性肾移植受体的生物标志物研究中富集的B细胞标志物一致。 我们提出的研究的总体目标是确定B细胞在诱导和维持移植耐受中的作用。第一个具体目标是确定选择性缺失成熟同种异体反应性B细胞的机制基础，并测试这种缺失是否对同种异体移植耐受的发展和/或维持是必需的。第二个目标是进一步表征保存的同种异体反应性B细胞。 未成熟/过渡期同种异体反应性B细胞，并测试这些细胞是否有助于移植耐受的发展或维持，我们认为这些研究将为B细胞在移植耐受中的作用提供见解，并有助于开发一种临床策略， 在没有药物免疫抑制的情况下移植物的长期存活，

Tolerance to allogeneic grafts can be achieved in a number of rodent models, and long-term graft survival has been reported in a number of non-human primate models, A consistent feature of stable graft acceptance is the control of alloantibody production; conversely, the appearance of increasing alloantibody titers portends graft rejection, Two divergent interpretations have been advanced to explain these observations- first, that the activation of alloreactive B cells and alloantibodies are simply markers of alloreactive T cell activation and that T cells are solely responsible for the loss of the allograft; second, alloreactive B cells and alloantibodies contribute to graft rejection; either directly or indirectly by synergizing with alloreactive T cells or other effector cells, Because of the well-characterized pathogenic properties of B cells and alloantibodies, we favor the second interpretation and hypothesize that the control of alloreactive B cells, in addition to T cells, is central to stable tolerance, Indeed, the unexpected efficacy of B cell-directed immunotherapy in controlling a number of autoimmune diseases and transplant rejection, pathologies initially thought to be predominantly T cellmediated, suggests an important role for B cells in these clinical settings, The fate of alloreactive T cells has been extensively defined in various models of transplantation tolerance, but there is virtually no information regarding the fate of alloreactive B cells, We have addressed this disparity by developing a novel experimental model to visualize the fate of alloreactive B cells, We observed that transplantation tolerance is associated with the deletion of the mature alloreactive B cells, and a sparing/enrichment of the transitional/immature alloreactive B cells, These observations are consistent with recent reports of a correlation between altered B cell subsets and tolerance in non-human primates and enriched B cell markers in bio-marker studies of spontaneously tolerant kidney transplant recipients, Thus the overall goal of our proposed studies is to define the role of B cells in the induction and maintenance of transplantation tolerance, The first specific aim is to define the mechanistic basis for the selective deletion of mature alloreactive B cells, and to test whether this deletion is essential for the development and/or maintenance of allograft tolerance, The second aim is to further characterize the preserved immature/transitional alloreactive B cells and test whether these cells contribute to the development or maintenance of tolerance, We antiCipate that these studies will provide insights into the role of B cells in transplantation tolerance, and contribute to the development of a clinical strategy that induces and maintains long-term graft survival in the absence of pharmacologic immunosuppression,