Selection and Regulation of B Lymphocytes in IDDM

描述(申请人提供)：IA型或胰岛素依赖型糖尿病(T1D)是由自身免疫过程破坏胰岛中产生胰岛素的细胞引起的。尽管已知T淋巴细胞介导T1D，但在T1D和其他T细胞介导的疾病中，B细胞定向治疗的成功使人们认识到B细胞在这些疾病中比之前认为的更重要。该实验室的研究重点是识别关键细胞自身抗原胰岛素的B淋巴细胞的功能。在NOD小鼠身上，来自胰岛素自身抗体的转基因被发现完全支持T1D的发展，而非胰岛素结合的Ig转基因不能。循环中的胰岛素和发育中的抗胰岛素B淋巴细胞之间的接触启动了一种免疫耐受状态，在这种状态下，自身反应性B细胞保留在免疫耐受库中，并向致病T细胞提供关键表位。一种针对胰岛素结合B细胞的特异性抗体阻止T1D的进展 在NOD小鼠身上。追踪多克隆谱系中的抗胰岛素B细胞，揭示了骨髓中心耐受性的缺陷，这是导致致病B细胞进入谱系的原因。这些发现表明，B淋巴细胞在T1D的发病机制中做出了以前未被认识到的贡献，并提出了一种假设，即这些特性可以被用来发现干预T1D的新靶点。这一假设将在三个具体目标上得到检验。首先，提供关键细胞表位的抗胰岛素B细胞将被用作糖尿病MHCII分子的来源，在这些分子上将使用质谱仪来识别B淋巴细胞提供的实际细胞表位。其次，自身抗原特异性B淋巴细胞将作为一种不同类型的靶点进行测试，以预防T1D并作为辅助治疗来帮助NOD患者逆转糖尿病。第三，NOD失败的中枢耐受机制将利用遗传和抗体介导的方法进行识别和修复。将这些研究结合起来，将在NOD小鼠模型中取得新的发现，该模型可以快速翻译用于人类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.