B Cell immunomodulation in islet transplantation

描述（由申请人提供）： 胰岛移植是1型糖尿病患者恢复正常血糖的最特异性治疗方法。尽管最近临床胰岛移植取得了成功，但即使在慢性免疫抑制的情况下，移植物长期存活仍然是一个难以实现的目标。因此，推进胰岛移植领域的一个主要目标是开发新的免疫干预策略，能够诱导永久性同种异体移植物存活，同时消除免疫抑制剂的长期使用。目前，胰岛移植免疫抑制治疗的主流包括用T淋巴细胞特异性抗体诱导，然后用T细胞特异性药理学试剂维持。这种“T细胞聚焦”方法是基于T淋巴细胞作为负责移植物排斥的效应群体的公认功能。尽管这种方法的逻辑，临床和实验数据清楚地表明，T细胞定向免疫抑制不能促进免疫耐受胰岛同种异体移植。在这里，我们认为，一个更平衡的考虑的适应性免疫反应的成分，以同种异体移植物提供了一个强有力的理由，一个综合的方法，免疫抑制：一个包括T-和B-淋巴细胞室。已经确定的是，除了同种异体反应性T细胞区室之外，宿主B淋巴细胞在移植后针对供体同种异体抗原产生强有力的免疫应答。尽管同种免疫应答的这一公认特征，但B淋巴细胞区室作为诱导免疫治疗的靶点在很大程度上被忽视。我们的初步探索性研究表明，宿主B淋巴细胞作为抗原提呈细胞在急性同种异体移植排斥反应的发病机制中起关键作用。此外，我们在非人灵长类动物接受者中的初步研究表明，使用抗CD 20 mAb（即，在诱导期使用利妥昔单抗（Rituxan）可促进胰岛移植物的长期存活，同时最大限度地减少对慢性免疫抑制的需求。这些结果迫使我们提出一种通过整合T-和B-淋巴细胞特异性抗体（即，Thymoglobulin和Rituxan）加入致耐受性方案中。在这个项目中，我们将在严格的临床前模型中确定这种诱导免疫治疗方案的有效性，并研究其促进非人灵长类动物胰岛移植物存活的机制基础。我们的总体观点是，在诱导阶段中断T和B淋巴细胞功能是一种新的和潜在的促进胰岛同种异体移植免疫耐受的有力手段。

DESCRIPTION (provided by applicant): Islet transplantation is the most specific therapy for restoration of euglycemia in patients with type 1 diabetes. Despite the recent success of clinical islet transplantation, achievement of long-term allograft survival remains an elusive goal even in the presence of chronic immunosuppression. Therefore, a major objective in advancing the field of islet transplantation is to develop novel immune intervention strategies capable of inducing permanent allograft survival while eliminating the chronic use of immunosuppressive agents. Presently the mainstay of immunosuppressive therapy for islet transplantation includes induction with T lymphocyte specific antibodies followed by maintenance with T cell specific pharmacological agents. This 'T-cell focused' approach is based on the well-established function of T lymphocytes as the effector population responsible for graft rejection. Notwithstanding the logic of this approach, both clinical and experimental data clearly indicate that T cell directed immunosuppression fails to promote immunological tolerance to islet allografts. Here, we suggest that a more balanced consideration of the components of the adaptive immune response to allografts provides a strong rationale for an integrated approach to immunosuppression: one including both the T- and B- lymphocyte compartments. It is well established that host B lymphocytes, in addition to the alloreactive T cell compartment, mount a robust immune response against donor alloantigens following transplantation. Despite this well-recognized feature of the alloimmune response, the B lymphocyte compartment has been largely neglected as a target of induction immunotherapy. Our preliminary exploratory studies have indicated that host B lymphocytes play a key role as antigen presenting cells in the pathogenesis of acute allograft rejection. Furthermore, our pilot studies in non-human primate recipients suggest that transient B lymphocyte depletion using an anti-CD20 mAb (i.e., Rituxan) at the induction phase promotes long-term islet allograft survival, while minimizing the need for chronic immunosuppression. These results have compelled us to propose a more balanced approach to induction immunotherapy by integrating both T- and B- lymphocyte specific antibodies (i.e., Thymoglobulin and Rituxan) into a tolerogenic regimen. In this project, we will determine the efficacy of such an induction immunotherapy regimen in a rigorous preclinical model and investigate its mechanistic basis in promoting islet allograft survival in non-human primates. Our overall contention is that interruption of T- and B- lymphocyte function during the induction phase represents a novel and potentially powerful means of promoting immunological tolerance to islet allografts.