B Cells and Type 1 Diabetes

B 细胞和 1 型糖尿病

• 批准号: 8372067
• 负责人: John C Cambier
• 金额: $ 32.51万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-20 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372067
• 关键词: Address; Affect; Affinity; American; Antigen Presentation; Antigen Receptors; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; Bone Marrow; CD4 Positive T Lymphocytes; Cell physiology; Cell surface; Cells; Clinical Trials; Development; Diabetes Mellitus; Diabetic mouse; Disease; Educational process of instructing; First Degree Relative; Flow Cytometry; Frequencies; Gene Transfer Techniques; Goals; Heavy-Chain Immunoglobulins; Human; Immune; Immune Tolerance; Immune system; Inbred NOD Mice; Individual; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Laboratories; Lymphoid; MS4A1 gene; Mediating; Modeling; Mus; Organ; Pancreas; Peripheral; Phenotype; Population; Predisposition; Role; Signal Pathway; Spleen; Surface; T-Lymphocyte; Techniques; Testing; To autoantigen; Treatment Efficacy; Work; adaptive immunity; anergy; base; cell type; central tolerance; diabetic; diabetic patient; functional status; insulin dependent diabetes mellitus onset; magnetic beads; non-diabetic; novel; prevent; research study; therapeutic effectiveness

DESCRIPTION (provided by applicant): Autoimmunity affects nearly ten million Americans and, for unknown reasons, is increasing in frequency. Available evidence indicates that autoimmune diseases arise due to a combination of genetically determined susceptibility and innate immune stimulation, which conspire to stimulate adaptive immunity to self. Underpinning autoimmunity is the breakdown of immune tolerance to self in T cell and/or B cell compartments. While a great deal is known about the mechanisms that maintain B cell tolerance, we understand little about the mechanisms that cause it to fail in autoimmunity. In this application we propose to study mechanisms operative in loss of B cell tolerance to insulin in murine and human Type 1 Diabetes, a disease known to require B cells that are thought to function by antigen presentation to CD4 T cells. Our approach will build upon our previous work defining signaling pathways operative in maintaining antigen unresponsiveness of anergic B cells. We will analyze by flow cytometry changes in the status of insulin-specific B cells isolated using a novel magnetic bead-based approach from normal, prediabetic and diabetic mice and patients. In some cases immunoglobulin heavy chain transgenesis will be used to generate a diverse antigen receptor repertoire that is nonetheless enriched in insulin-specific cells. Aim 1 will explore how peripheral insulin-specific B cells are silenced in normal mice and whether this silencing is breached in diabetic mice. In Aim 2 we will study the role of antigen receptor affinit for insulin in determining mode of silencing, fate and diabetogenic potential. This will involve a retrotransgenic approach to generate a repertoire with defined antigen receptor affinity for insulin. In Aim 3 we will extend studies to the human, comparing insulin-specific B cells in prediabetic and diabetic individuals to non-diabetic first- degree relatives. Finally, in Aim 4 we will assess the therapeutic efficacy in T1D of a novel B cell desensitizing therapy, comparing this therapy to anti-CD20, which depletes B cells. The experiments will address the overarching hypothesis that in Type 1 Diabetes the silence of high affinity insulin-specific B cells is broken and these cells promote disease by presentation of autoantigen to CD4 T cells. PUBLIC HEALTH RELEVANCE: Type 1 Diabetes (T1D) is an autoimmune disease in which insulin-producing cells in the pancreas are attacked by the immune system. While T lymphocytes are responsible for actual organ damage, insulin-specific B cells are required for development of the disease. This application proposes analysis of the role of these B cells in TID, and will test the therapeutic effectiveness of a novel B cell-targeted therapy in this disease

描述(申请人提供)：自身免疫性疾病影响着近1000万美国人，并且由于未知的原因，其发生的频率正在增加。现有证据表明，自身免疫性疾病的发生是由于遗传决定的易感性和先天免疫刺激的结合，这些刺激共同刺激对自身的适应性免疫。自身免疫的基础是T细胞和/或B细胞对自身免疫耐受性的崩溃。虽然我们对维持B细胞耐受的机制了解很多，但我们对导致B细胞自身免疫失败的机制知之甚少。在这项应用中，我们建议研究在小鼠和人类1型糖尿病中B细胞对胰岛素耐受性丧失的机制，这种疾病被认为需要B细胞通过向CD4T细胞递送抗原来发挥作用。我们的方法将建立在我们之前的工作基础上，定义在维持无能B细胞的抗原不反应中起作用的信号通路。我们将通过流式细胞术分析从正常、糖尿病前期和糖尿病小鼠和患者中使用一种新的磁珠方法分离的胰岛素特异性B细胞的状态变化。在某些情况下，免疫球蛋白重链转基因将被用来产生不同的抗原受体谱系，尽管如此，胰岛素特异细胞中仍有丰富的抗原受体谱系。目的1将探索正常小鼠外周胰岛素特异性B细胞是如何沉默的，以及糖尿病小鼠是否打破了这种沉默。在目标2中，我们将研究胰岛素的抗原受体亲和力在决定沉默模式、命运和致糖尿病潜能中的作用。这将涉及一种逆转录转基因方法，以产生具有明确的胰岛素抗原受体亲和力的谱系。在目标3中，我们将研究扩展到人类，将糖尿病前期和糖尿病患者的胰岛素特异性B细胞与非糖尿病患者的一级亲属进行比较。最后，在目标4中，我们将评估一种新的B细胞脱敏疗法在T1D中的治疗效果，并将该疗法与耗尽B细胞的抗CD20进行比较。这些实验将解决最主要的假设，即在1型糖尿病中，高亲和力胰岛素特异性B细胞的沉默被打破，这些细胞通过将自身抗原呈递给CD4T细胞而促进疾病。 公共卫生相关性：1型糖尿病(T1D)是一种自身免疫性疾病，胰腺中的胰岛素产生细胞受到免疫系统的攻击。虽然T淋巴细胞是造成实际器官损害的罪魁祸首，但胰岛素特异性B细胞是疾病发展所必需的。这项应用提出了对这些B细胞在TID中的作用的分析，并将测试一种新的B细胞靶向治疗在这种疾病中的疗效