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）是由自身免疫过程破坏胰岛中产生胰岛素的细胞引起的。虽然已知T淋巴细胞介导T1D，但B细胞定向治疗T1D和其他T细胞介导的疾病的成功使人们认识到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小鼠实验中，发现胰岛素自身抗体的转基因完全支持T1D的发展，而非胰岛素结合的Ig转基因则不支持。循环胰岛素和发展中的抗胰岛素B淋巴细胞之间的接触启动了免疫耐受状态，在这种状态下，自身反应性B细胞保留在库中，并向致病性T细胞呈递关键的表位。一种针对胰岛素结合B细胞的特异性抗体可阻断T1D的进展

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.