Targeting Blys/Baff in non-human primate islet transplantation

描述(申请人提供)：胰岛移植是β细胞替代和实现血糖稳态的最特异的治疗方法。然而，尽管T细胞导向的免疫治疗，大多数同种异体胰岛移植物都会发生排斥反应，通常伴随着供者特异性免疫球蛋白同种抗体的产生，这些抗体除了被认为是预后较差的临床指标外，还被认为在体内发挥了致病作用。我们在小鼠模型中的初步研究表明，B细胞抗原提呈在同种异体反应性CD4T淋巴细胞活化中起着必要的作用。因此，我们的论点是，诱导强大的移植耐受将需要在B细胞和T细胞水平上都没有反应。因此，我们利用诱导免疫疗法对食蟹猴进行了胰岛移植的临床前试验，其中包括一种CD20特异性B细胞去除剂。这项试验的结果表明，在短暂性B细胞耗尽时， 移植可在相当长的时间内保护同种异体胰岛移植物免受排斥反应。然而， 大多数受者最终产生供者特异性的同种异体抗体，这与胰岛移植功能的丧失是一致的。因此，本应用的主要机制主张是建立B细胞耐受是实现对同种异体胰岛移植的免疫耐受所必需的。我们的目标是开发一种临床上可行的、以B细胞为导向的免疫治疗策略，其基础是控制B细胞对自身抗原耐受性的动态平衡机制。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控途径来诱导供者特异性的B细胞耐受： 肿瘤坏死因子相关细胞因子BLyS/BAFF。最近人们认识到，这种细胞因子调节抗原介导的对新出现的“过渡性”B细胞的负选择，从而成为形成成熟B细胞系的主要微环境线索。在此，我们假设在胰岛移植物存在的情况下，在B细胞室重建过程中限制系统BLyS/BAFF的可用性将促进B细胞耐受的持续状态。我们将在食蟹猴的同种异体胰岛移植中测试这一具有临床意义的概念。 公共卫生相关性：拒绝移植器官给美国的公共卫生资源带来了重大负担。此外，要求终生免疫抑制以维持移植功能，不仅给卫生保健系统带来了重大的成本负担，而且还给接受者带来了严重的发病率。在这一应用中，我们提出了一种新的研究途径，通过靶向受体B淋巴细胞来诱导供者对同种异体移植物的特异性免疫耐受。

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. PUBLIC HEALTH RELEVANCE: The rejection of transplanted organs places a major burden on public health resources in the United States. Furthermore, the requirement for life-long immunosuppression to maintain transplant function not only poses a major cost burden on the health care system, but also imposes a dramatic degree of morbidity on the recipient. In this application, we propose a novel avenue of investigations into the possibility of inducing donor specific immunological tolerance to allografts by targeting recipient B-lymphocytes.