Bruton's Tyrosine Kinase and Immune Tolerance in Type 1 Diabetes

布鲁顿酪氨酸激酶和 1 型糖尿病的免疫耐受

• 批准号: 8776292
• 负责人: Peggy L Kendall
• 金额: $ 32.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-27 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776292
• 关键词: Address; Adoptive Transfer; Agammaglobulinaemia tyrosine kinase; Amino Acids; Antigen Presentation; Antigens; Autoantibodies; Autoantigens; Autoimmune Diabetes; B cell repertoire; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Assay; Cell physiology; Cells; Clinical; Complement 3d Receptors; Complex; Dependence; Development; Diabetes Mellitus; Disease; Disease Progression; Effectiveness; Employee Strikes; Event; Goals; Health; Immune Tolerance; Immunoglobulin G; Inbred NOD Mice; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islet Cell; Knock-out; Lead; Link; Mature B-Lymphocyte; Mediating; Modeling; Molecular; Mus; Outcome; Phosphotransferases; Play; Process; Property; Receptor Signaling; Receptors, Antigen, B-Cell; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Staging; System; T-Lymphocyte; Testing; Therapeutic Intervention; Transgenic Mice; Transgenic Model; Transgenic Organisms; Tyrosine Kinase Domain; Tyrosine Kinase Inhibitor; adapter protein; antigen binding; autoreactive B cell; autoreactivity; base; islet; mouse model; novel; prevent; reconstitution; research study; response; small molecule; tool

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) results from a complex cascade of events that breaks immune tolerance and culminates in the destruction of islet 2 cells. B lymphocytes (B cells) play a critical role in disease development, probably via antigen-presentation to pathogenic T cells. B cell contribution to the development of diabetes depends upon multiple factors, including loss of tolerance to self antigen. This tolerance is mediated by cellular responses to antigen-binding via the B cell receptor (BCR). Bruton's tyrosine kinase (BTK) is a central component of the BCR-triggered signaling pathway. Understanding cell signaling components underlying B cell-driven diabetes development will advance the field toward specific targeting of pathogenic B cells. We have introgressed btk-deficiency onto the nonobese diabetic (NOD) mouse model of T1D, and found that this results in significant protection against the development of diabetes. In addition, btk-deficiency interferes with B cell related breaches of immune tolerance, as evidenced by the loss of insulin-specific IgG autoantibodies in wild type NOD mice, and reduction of insulin-binding B cells in a transgenic anti-insulin BCR model. The specific hypothesis underlying this proposal is that BTK-mediated propagation of BCR signals contributes to 1) selection and survival of autoreactive B lymphocytes, and 2) disease- promoting functional properties of these B cells. To understand the mechanisms of action of BTK in breaking B lymphocyte tolerance and promoting disease in autoimmune diabetes, we propose to: 1) discover how BTK participates in the selection and retention of autoreactive B lymphocytes, using use new tools that include a conditional, B cell-specific BTK knockout model and small molecule BTK- inhibitors, 2) determine which domains of the BTK molecule are responsible for autoreactive B lymphocyte selection and function, by systematically restoring independent components responsible for the kinase and linking functions, and 3) investigate the mechanisms of btk-deficiency in preventing T1D by examining effects on B cell subsets, antigen-presenting outcomes, and regulatory parameters. This project has direct clinical importance in understanding how BCR-signaling supports the selection, survival and function of autoreactive B cells in T1D, as a necessary step in developing therapeutic interventions.

描述（由申请人提供）：1 型糖尿病 (T1D) 是由一系列复杂的事件引起的，这些事件破坏了免疫耐受并最终导致胰岛 2 细胞的破坏。 B 淋巴细胞（B 细胞）在疾病发展中发挥着关键作用，可能是通过将抗原呈递给致病性 T 细胞来实现的。 B 细胞对糖尿病发展的贡献取决于多种因素，包括丧失对自身抗原的耐受性。这种耐受性是由 B 细胞受体 (BCR) 对抗原结合的细胞反应介导的。布鲁顿酪氨酸激酶 (BTK) 是 BCR 触发信号通路的核心组成部分。了解 B 细胞驱动的糖尿病发展背后的细胞信号传导成分将推动该领域朝着特异性靶向致病性 B 细胞的方向发展。我们将 btk 缺陷基因渗入到 T1D 的非肥胖糖尿病 (NOD) 小鼠模型中，发现这可以显着预防糖尿病的发展。此外，btk 缺陷会干扰 B 细胞相关的免疫耐受破坏，野生型 NOD 小鼠中胰岛素特异性 IgG 自身抗体的丧失以及转基因抗胰岛素 BCR 模型中胰岛素结合 B 细胞的减少就证明了这一点。该提议的具体假设是，BTK 介导的 BCR 信号传播有助于 1) 自身反应性 B 淋巴细胞的选择和存活，以及 2) 这些 B 细胞的疾病促进功能特性。为了了解 BTK 在破坏 B 淋巴细胞耐受性和促进自身免疫性糖尿病疾病方面的作用机制，我们建议：1) 使用包括条件性 B 细胞特异性 BTK 敲除模型和小分子 BTK 抑制剂在内的新工具，发现 BTK 如何参与自身反应性 B 淋巴细胞的选择和保留，2) 确定 BTK 的哪些域 BTK 分子通过系统地恢复负责激酶和连接功能的独立成分，负责自身反应性 B 淋巴细胞的选择和功能，3) 通过检查对 B 细胞亚群、抗原呈递结果和调节参数的影响，研究 btk 缺陷预防 T1D 的机制。该项目对于了解 BCR 信号传导如何支持 T1D 中自身反应性 B 细胞的选择、存活和功能具有直接的临床重要性，是开发治疗干预措施的必要步骤。