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: 8886719
• 负责人: Peggy L Kendall
• 金额: $ 22.15万
• 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 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886719
• 关键词: Adoptive Transfer; Adult; Affect; Agammaglobulinaemia tyrosine kinase; Antibodies; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; B-Lymphocytes; Bacteria; Beta Cell; Cells; Clinical; Complex; Development; Diabetes Mellitus; Disease; Disease Outcome; Event; Excision; Exposure to; Gene Deletion; Genetic; Germ-Free; Goals; Growth; Immune; Immune Tolerance; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Inbred NOD Mice; Infectious Agent; Insulin; Insulin-Dependent Diabetes Mellitus; Integration Host Factors; Intervention; Intestines; Investigation; Islets of Langerhans; Kinetics; Left; Link; Mediating; Microbe; Microbial Genome Sequencing; Modeling; Modification; Monozygotic twins; Mucosal Immunity; Mucous Membrane; Neonatal; Non obese; Outcome; Pharmaceutical Preparations; Play; Population; Production; Role; Shapes; Signal Transduction; Signaling Protein; Staging; Structure; Structure of aggregated lymphoid follicle of small intestine; Surface; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Tyrosine Kinase Inhibitor; adaptive immunity; autoreactive B cell; autoreactive T cell; diabetic; experience; gut microbiota; islet; microbial; microbiome; neonatal exposure; neonate; novel; novel strategies; pathogen; prevent; public health relevance; reconstitution; research study

 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 ß cells. B lymphocytes (B cells) play a critical role in disease. This project focuses on the role ofa central B cell signaling protein, Bruton's tyrosine kinase (BTK). We have defined the role of BTK in supporting autoreactive B cells that present antigen to autoreactive T cells, and shown that BTK can be targeted to protect against development of T1D. We now extend those findings to mucosal immunity, and have discovered that BTK-deficient nonobese diabetic (NOD) mice have greatly reduced numbers of Peyer's Patch B cells, important for production of IgA. Accordingly, IgA is also reduced. We therefore tested the hypothesis that IgA in gut mucosa selects the resident microbes. Genetic sequencing of intestinal microbiota showed that Btk-/-/NOD mice have strikingly altered microbial populations compared with wild type NOD mice. Furthermore, exposure to different microbes in the neonatal period abrogated disease protection in Btk-/-/NOD mice. The hypothesis underlying this proposal is that B cell signaling via BTK supports production of IgA, which shapes a microbiome that promotes T1D in genetically susceptible hosts. To understand BTK contributions to the microbiome in relationship to T1D, we propose to: 1) determine the mechanisms by which BTK regulates the microbiome, by using cell-specific targeted deletion to define the effects on gut immune structures including Peyer's Patches. The impact of BTK actions on IgA production and gut immune responses will be investigated and effects of BTK inhibitors on mucosal immunity assessed, 2) determine the kinetics of BTK-targeting in modifying the microbiome. The developmental stages from neonate to adult when the microbiome is sensitive to the functions of BTK will be identified. Timed excision of BTK or drug administration will assess the potential to halt the progression of T1D in the NOD model and determine if microbiome modification is required for a successful outcome. Experiments will also determine how reconstitution with PP B cells affects microbial modification and disease outcome, and 3) determine disease contributions of the microbiome that is supported by BTK. Btk-/-/NOD mice will be rederived into a germ-free facility to separate autoimmune disease effects of BTK-signaling from that of the microbiome. Fecal transfer will be used to directly test microbiome contributions to T1D. This project has direct clinical importance in understanding how BCR-signaling supports the selection of commensal flora that influences the outcome of T1D as a necessary step in developing therapeutic interventions.

 描述（由适用提供）：1型糖尿病（T1D）是由一系列复杂的事件级联产生的，这些事件破坏了免疫耐受性并在胰岛细胞的破坏中达到顶点。 B淋巴细胞（B细胞）在疾病中起关键作用。该项目着重于中央B细胞信号蛋白Bruton的酪氨酸激酶（BTK）的作用。我们已经定义了BTK在支持对自动反应性T细胞抗原的自动反应性B细胞中的作用，并表明BTK可以靶向以防止T1D的发展。现在，我们将这些发现扩展到粘膜免疫，并发现BTK缺陷型非肥胖糖尿病（NOD）小鼠的佩耶斑块B细胞数量大大减少，这对于IgA的产生很重要。据此，IGA也减少了。因此，我们测试了肠粘膜中IgA选择居民微生物的假设。肠道菌群的遗传测序表明，与野生型NOD小鼠相比，BTK - / - /NOD小鼠的微生物种群发生了巨大改变。此外，在新生儿时期暴露于不同的微生物中，废除了BTK的疾病保护 - / - /NOD小鼠。该提案的基础假设是BTK通过BTK的B细胞信号传导支持IGA的产生，IgA塑造了一个微生物组，该微生物组促进了在一般易感宿主中促进T1D。为了了解BTK对微生物组与T1D的关系的贡献，我们建议：1）通过使用细胞特异性的靶向缺失来确定BTK调节微生物组的机制，以定义对包括Peyer斑块在内的肠道免疫结构的影响。将研究BTK作用对IGA产生和肠道免疫调查的影响，并将BTK抑制剂对粘膜免疫评估的影响，2）确定在修饰微生物组时确定靶向BTK靶向的动力学。当微生物组对BTK功能敏感时，从新生儿到成人的发育阶段将被确定。 BTK或药物管理的定时惊喜将评估停止NOD模型中T1D进展的潜力，并确定成功结果是否需要微生物组修饰。实验还将确定与PP B细胞的重建如何影响微生物的修饰和疾病结果，3）确定BTK支持的微生物组的疾病贡献。 BTK - / - /NOD小鼠将被重新融合到无菌的设施中，以将BTK信号的自身免疫性疾病与微生物组的自身免疫性疾病作用分开。粪便转移将用于直接测试微生物组对T1D的贡献。该项目在理解BCR信号如何支持Consensal Flora的选择方面具有直接的临床重要性，该植物会影响T1D作为开发治疗的必要步骤。干预措施。