Selection and Regulation of B Lymphocytes in IDDM

描述（由申请人提供）：IA型或胰岛素依赖型糖尿病（T1D）是由破坏胰岛中产生胰岛素的细胞的自身免疫过程引起的。尽管已知T淋巴细胞介导T1D，但T1D和其他T细胞介导的疾病中B细胞导向疗法的成功已导致认识到B细胞在这些疾病中比以前认为的更重要。本实验室的研究重点是B淋巴细胞识别关键细胞自身抗原胰岛素的功能。使用NOD小鼠，发现来自胰岛素自身抗体的转基因完全支持T1D的发展，而非胰岛素结合IG转基因则不支持。循环胰岛素和发育中的抗胰岛素B淋巴细胞之间的相遇引发免疫耐受状态，其中自身反应性B细胞保留在库中并将关键表位呈递给病原性T细胞。特异性靶向胰岛素结合B细胞的特异性抗体阻断T1 D的进展 NOD小鼠。在多克隆库中追踪抗胰岛素B细胞揭示了骨髓中负责将致病性B细胞接种到库中的中枢耐受性的缺陷。这些发现揭示了B淋巴细胞对T1D的发病机制做出了以前未被认识的贡献，并提出了一种假设，即可以利用这些特性来发现T1D干预的新靶点。这一假设将在三个具体目标中得到检验。首先，呈现关键的细胞表位的抗胰岛素B细胞将被用作致糖尿病MHCII分子的来源，质谱法将用于鉴定B淋巴细胞呈现的实际细胞表位。第二，将测试自身抗原特异性B淋巴细胞作为T1D预防的不同类型的靶点，并作为辅助NOD中糖尿病逆转的联合治疗。第三，将使用遗传和抗体介导的方法鉴定和修复NOD中失败的中枢耐受机制。结合这些研究将在NOD小鼠模型中取得新的发现，可以快速转化用于人类T1D。

DESCRIPTION (provided by applicant): Type IA or insulin dependent diabetes (T1D) is caused by an autoimmune process that destroys insulin-producing ¿ cells in the pancreatic islets. Although T lymphocytes are known to mediate T1D, success with B cell directed therapy in T1D and other T cell-mediated disorders has led to the recognition that B cells are more important in these diseases than previously thought. Research in this laboratory is focused on function of B lymphocytes that recognize the key ¿ cell autoantigen, insulin. Using NOD mice, transgenes from an insulin autoantibody were discovered to fully support the development of T1D while non-insulin binding Ig- transgenes do not. Encounters between circulating insulin and developing anti-insulin B lymphocytes initiates a state of immune tolerance in which the autoreactive B cells remain in the repertoire and present critical epitopes to pathogenic T cells. A specific antibody that specifically targets insulin-binding B cells blocks the progression of T1D in NOD mice. Tracking anti-insulin B cells in a polyclonal repertoire reveals flaws in central tolerance in the bone marrow that is responsible for seeding pathogenic B cells into the repertoire. These findings reveal that B lymphocytes make previously unappreciated contributions the pathogenesis of T1D and suggest a hypothesis that these properties can be exploited to discover new targets for intervention in T1D. This hypothesis will be test in three specific aims. First, anti-insulin B cells that present critical ¿ cell epitopes will be used as a source of diabetogenic MHCII molecules on which mass spectrometry will be used to identify actual ¿ cell epitopes presented by B lymphocytes. Second, autoantigen specific B lymphocytes will be tested as a different type of target for T1D prevention and as a co-therapy to assist in reversal of diabetes in NOD. Third, the mechanisms of central tolerance that fail in NOD will be identified and repaired using genetic and antibody mediated approaches. Combined these studies will make new discoveries in the NOD mouse model that can be rapidly translated for use in human T1D.