B Cells in Transplantation Tolerance

在一些啮齿动物模型中可以实现对同种异体移植物的耐受，并且在一些非人类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个一致的特征是控制同种异体抗体的产生；相反，同种异体抗体效价的增加预示着同种异体抗体的出现 关于移植物排斥，有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激活只是同种异体反应性T细胞激活的标志，T细胞是移植物丧失的唯一原因；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反应；无论是直接还是间接通过与同种异体反应性T细胞或其他效应细胞的协同作用，由于B细胞和同种异体抗体的致病特性，我们赞成第二种解释和假设，即除了T细胞之外，控制同种异体反应性B细胞是稳定耐受的核心，确实，B细胞定向免疫疗法在控制许多同种异体反应性T细胞的免疫反应方面具有意想不到的效果。 自身免疫性疾病和移植排斥，最初被认为是主要由T细胞介导的病理，表明B细胞在这些临床环境中扮演着重要的角色。同种异体反应性T细胞的命运在各种移植耐受模型中得到了广泛的定义，但几乎没有关于同种异体反应性B细胞的命运的信息。我们已经通过开发一种新的实验模型来可视化同种异体反应性B细胞的命运来解决这一差异，我们观察到 移植耐受与成熟的同种异体反应性B细胞的缺失，以及过渡性/未成熟的同种异体反应性B细胞的保留/浓缩有关，这些观察结果与最近报道的在自然耐受肾移植受者的生物标志物研究中改变的B细胞亚群与非人类灵长类动物的耐受性和丰富的B细胞标志物之间的相关性是一致的。 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删除成熟的同种异体反应性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形成和/或维持是必要的，第二个目标是进一步描述保存的 对于未成熟/过渡性同种异体反应性B细胞，并测试这些细胞是否有助于耐受的形成或维持，我们预计这些研究将为深入了解B细胞在移植耐受中的作用提供帮助，并有助于制定诱导和维持移植耐受的临床策略 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,