B Cell immunomodulation in islet transplantation

描述(由申请人提供)： 胰岛移植是恢复1型糖尿病患者正常血糖的最特异的治疗方法。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，实现同种异体移植物的长期存活仍然是一个难以实现的目标。因此，发展新的免疫干预策略是推进胰岛移植领域的一个主要目标，该策略能够在消除长期使用免疫抑制剂的同时，诱导同种异体移植物的永久存活。目前，胰岛移植的免疫抑制治疗主要包括T淋巴细胞特异性抗体诱导和T细胞特异性药物维持治疗。这种“以T细胞为中心”的方法是基于T淋巴细胞作为移植物排斥反应的效应细胞群的公认功能。尽管有这种方法的逻辑，但临床和实验数据都清楚地表明，T细胞导向的免疫抑制未能促进对同种异体胰岛移植物的免疫耐受。在这里，我们建议，对同种异体移植的适应性免疫反应的组成部分的更平衡的考虑为免疫抑制的综合方法提供了强有力的理论基础：一种包括T和B淋巴细胞室的方法。在移植后，宿主B淋巴细胞，除了同种异体反应性T细胞室外，对供体同种异体抗原也有很强的免疫反应。尽管同种异体免疫反应的这一众所周知的特征，但作为诱导免疫治疗的目标，B淋巴细胞室在很大程度上被忽视了。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同种异体急性排斥反应的发病机制中起着关键作用。此外，我们在非人类灵长类受体中的初步研究表明，在诱导阶段使用抗CD20单抗(即Rituxan)的瞬时B淋巴细胞耗竭可促进同种异体胰岛移植物的长期存活，同时最大限度地减少慢性免疫抑制的需要。这些结果迫使我们提出了一种更平衡的诱导免疫治疗方法，将T和B淋巴细胞特异性抗体(即胸腺球蛋白和Rituxan)整合到耐受方案中。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，并探讨其在促进非人类灵长类动物同种异体胰岛移植存活方面的机制基础。我们的总体观点是，在诱导阶段阻断T和B淋巴细胞的功能是促进同种异体胰岛移植物免疫耐受的一种新的和潜在的有效手段。

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.