Selection and Regulation of B Lymphocytes in IDDM

IDDM 中 B 淋巴细胞的选择和调节

• 批准号: 9252782
• 负责人: James W Thomas
• 金额: $ 17.39万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252782
• 关键词: Antibodies; Autoantibodies; Autoantigens; Autoimmune Process; B-Lymphocytes; Binding; Bone Marrow; CD3 Antigens; CD4 Positive T Lymphocytes; Cell physiology; Cells; Child; Coupled; Development; Diabetes Mellitus; Diagnosis; Disease; Disease remission; Engineering; Epitopes; Excision; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Health; Homeostasis; Human; Immune; Immune Tolerance; Immunologic Receptors; Immunosuppression; In Vitro; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islets of Langerhans; Knowledge; Laboratories; Libraries; MS4A1 gene; Mass Spectrum Analysis; Mediating; Mus; PTPN22 gene; Pathogenesis; Peptides; Physiological; Prevention; Production; Property; Receptor Signaling; Regulation; Research; Resources; Seeds; Source; Specificity; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Transgenes; Translating; Vaccines; adaptive immunity; autoreactive B cell; central tolerance; congenic; diabetogenic; dosage; feeding; high risk; improved; in vivo; mouse model; novel; optimism; peptide structure; preproinsulin; prevent; receptor; repaired; research study; success; weapons

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.

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 B 细胞定向治疗在 T1D 和其他 T 细胞介导的疾病中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。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。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 转基因则不然。循环中的胰岛素和发育中的抗胰岛素 B 淋巴细胞之间的相遇会引发一种免疫耐受状态，其中自身反应性 B 细胞保留在所有功能中，并向致病性 T 细胞呈递关键表位。一种专门针对胰岛素结合 B 细胞的特异性抗体可阻止 T1D 的进展 在NOD小鼠中。追踪多克隆库中的抗胰岛素 B 细胞揭示了骨髓中枢耐受性的缺陷，该缺陷负责将致病性 B 细胞播种到该库中。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到的贡献，并提出了一个假设，即可以利用这些特性来发现干预 T1D 的新靶点。该假设将在三个具体目标上进行检验。首先，呈现关键细胞表位的抗胰岛素 B 细胞将被用作糖尿病性 MHCII 分子的来源，并使用质谱法来识别 B 淋巴细胞呈现的实际细胞表位。其次，将测试自身抗原特异性 B 淋巴细胞作为 T1D 预防的不同类型靶标以及作为协助逆转 NOD 糖尿病的联合疗法。第三，NOD 中失败的中枢耐受机制将通过遗传和抗体介导的方法进行识别和修复。这些研究相结合，将在 NOD 小鼠模型中取得新发现，并可快速转化为用于人类 T1D。