Targeting Blys/Baff in non-human primate islet transplantation

非人灵长类胰岛移植中的靶向 Blys/Baff

基本信息

批准号：
9113465
负责人：
Ali Naji
金额：
$ 94.7万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113465
关键词：
Achievement Acute Alloantigen Allografting Antigen Presentation Antigen-Presenting Cells Antigens Autoantigens B cell repertoire B-Cell Development B-Lymphocytes Beta Cell CD4 Positive T Lymphocytes Cell Ontogeny Cell Survival Clinical Clonal Deletion Cues Development Exclusion Family member Goals Graft Rejection Health Resources Healthcare Systems Homeostasis Immunoglobulin G Immunosuppression Immunotherapeutic agent Immunotherapy Insulin-Dependent Diabetes Mellitus Investigation Islets of Langerhans Transplantation Isoantibodies Length Life Longevity MS4A1 gene Macaca Macaca fascicularis Mature B-Lymphocyte Mediating Modality Morbidity - disease rate Organ Transplantation Pathogenesis Pathway interactions Predisposition Production Public Health Regimen Regulation Regulatory Pathway Role Serum Shapes Specificity Staging T-Lymphocyte TALL-1 protein TNF gene Testing Therapeutic Time Transplantation Transplantation Tolerance United States allograft rejection base belimumab beta cell replacement blood glucose regulation cost cytokine graft function in vivo islet islet allograft meetings mouse model nonhuman primate novel preclinical trial prognostic reconstitution response standard of care

项目摘要

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.

描述（由申请人提供）：胰岛移植是β细胞替代和葡萄糖稳态实现的最具体疗法。然而，尽管T细胞定向免疫疗法，但大多数胰岛移植物，屈服于排斥〜通常与产生供体特异性IgG同种异体抗体同时发生，除了较差的预后临床指标外，还被认为是在VIVO中发挥致病性作用。我们在鼠模型中的初步研究表明，B细胞抗原表现在激活中的必要作用O同种异体CD4淋巴细胞。因此，我们的论点是，稳健移植耐受性的诱导将需要在B和T细胞室的水平上无反应。因此，我们利用诱导免疫疗法方案进行了cynomolgus猕猴的胰岛移植试验，其中包括CD20特异性B细胞耗竭剂。该试验的结果表明，瞬时B细胞在移植可保护胰岛同种异体移植物在很大的时间长度上拒绝。然而，最终在大多数接受者中产生了供体特异性IgG同抗体，这与胰岛移植功能的丧失一致。因此，当前应用的主要机械命题是建立B细胞耐受性才能实现对胰岛同种异体移植的免疫耐受性。我们的目标是基于管理B细胞耐受性对自我抗原的耐受性的稳态机制，开发一种临床上可行的，B细胞指导的免疫治疗策略。为此，我们旨在通过靶向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细胞的耐受性： TNF相关的细胞因子称为Blys/Baff。最近，人们认识到，这种细胞因子调节了新出现的“过渡” B细胞的抗原介导的负选择，因此作为主要的微环境提示，负责塑造成熟的B细胞库。在这里，我们假设限制在同种异体移植物存在下B细胞室重建过程中全身性BLYS/BAFF的可用性将促进B细胞耐受性的持续状态。我们将在cynomolgus猴子胰岛转移的环境中测试这种临床上相关的概念。