Targeting Blys/Baff in non-human primate islet transplantation

描述（由申请人提供）：胰岛移植是β细胞替代和实现葡萄糖稳态的最特异性疗法。然而，尽管有T细胞导向的免疫疗法，大多数胰岛同种异体移植物还是会发生排斥反应，通常与供体特异性IgG同种异体抗体的产生同时发生，这除了是不良预后临床指标外，还被认为在体内发挥致病作用。我们在小鼠模型中的初步研究表明B细胞抗原呈递在同种异体反应性CD 4 T淋巴细胞活化中的必要作用。因此，我们的论点是，强大的移植耐受的诱导将需要在B-和T-细胞室的水平上的无反应性。因此，我们利用诱导免疫治疗方案在食蟹猴中进行了胰岛移植的临床前试验，该方案包括CD 20特异性B细胞耗竭剂。该试验的结果表明，在治疗时短暂的B细胞耗竭 移植在相当长的时间内保护胰岛同种异体移植物免于排斥。然而，在这方面， 在大多数受体中最终产生供体特异性IgG同种抗体，与胰岛移植物功能的丧失一致。因此，本申请的主要机制主张是，需要建立B细胞耐受性以实现对胰岛同种异体移植物的免疫耐受性。我们的目标是开发一种临床上可行的，B细胞导向的免疫策略的基础上的自我平衡机制的发展B细胞耐受性的自我抗原。为此，我们的目标是通过靶向B细胞存活、寿命和选择的关键调节途径来诱导供体特异性B细胞耐受： 称为BLyS/BAFF的TNF相关细胞因子。最近认识到，这种细胞因子调节抗原介导的新出现的“过渡”B细胞的阴性选择，从而充当负责形成成熟B细胞库的主要微环境因子。在此，我们假设在胰岛同种异体移植物存在的情况下，在B细胞区室重建期间限制全身BLyS/BAFF的可用性将促进B细胞耐受的持续状态。我们将在食蟹猴的胰岛异体移植中测试这一临床相关概念。

DESCRIPTION (provided by applicant): Islet transplantation is the most specific therapy for beta cell replacement and achievement of glucose homeostasis. However, despite a T cell-directed immunotherapy, majority of islet allografts, succumb to rejection~ typically co-incident with the production of donor specific IgG alloantibodies, which in addition to being poor prognostic clinical indicators are thought to exert a pathogenic role in vivo. Our preliminary studies in a murine model indicated a requisite role of B-cell antigen presentation in activation o alloreactive CD4 T lymphocytes. Therefore, our contention is that the induction of robust transplantation tolerance will require unresponsiveness at the level of both the B- and T-cell compartments. As such, we performed a preclinical trial of islet transplantation in Cynomolgus macaques utilizing an induction immunotherapy regimen, which included a CD20 specific B cell depleting agent. The results of this trial indicated that transient B cell depletion at the time of transplantation protects islet allografts from rejection for a significant length of time. However, donor-specific IgG alloantibodies were eventually produced in the majority of the recipients, coincident with the loss of islet graft function. Therefore, the main mechanistic proposition of th present application is that establishment of B cell tolerance is required for achievement of immunological tolerance to islet allografts. Our goal is to develop a clinically feasible, B cell-directed immunotherapeutic strategy based on the homeostatic mechanisms governing the development of B cell tolerance to self-antigens. To this end, we aim to induce donor-specific B cell tolerance by targeting the key regulatory pathway of B cell survival, life-span and selection: the TNF-related cytokine known as BLyS/BAFF. It was recently recognized that this cytokine regulates antigen mediated negative selection of newly emerging "transitional" B cells and, thereby, serves as the major micro-environmental cue responsible for shaping the mature B cell repertoire. Here, we hypothesize that limiting the availability of systemic BLyS/BAFF during B cell compartment reconstitution in the presence of an islet allograft will promote a sustained state of B cell tolerance. We will test this clinically pertinent concept in the setting of islet alo-transplantation in Cynomolgus monkeys.