B Cell Traffic in Type I Diabetes Mellitus

I 型糖尿病中的 B 细胞流量

• 批准号: 7579889
• 负责人: Peggy L Kendall
• 金额: $ 12.5万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579889
• 关键词: Adoptive Transfer; Affect; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Autoimmune Process; Automobile Driving; B-Lymphocytes; Benign; Beta Cell; Binding; CXCL13 gene; Cell Death; Chemotactic Factors; Confocal Microscopy; Dendritic Cells; Dependence; Development; Diabetes Mellitus; Diabetic mouse; Disease; Disease Outcome; Engineering; Genetic Techniques; Goals; Image; Imagery; Immigration; Immunoglobulins; In Vitro; Inbred NOD Mice; Individual; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Invaded; Islets of Langerhans; Lymphocyte; Lymphoid Follicle; Lymphoid Tissue; Mediating; Molecular; Mus; Non obese; Onset of illness; Pancreas; Pathologic Processes; Pathway interactions; Play; Process; Receptors, Antigen, B-Cell; Recruitment Activity; Research Personnel; Rheumatoid Arthritis; Role; Serological; Signal Transduction; Site; Sjogren' s Syndrome; Specificity; Structure of beta Cell of islet; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Transgenes; Transgenic Organisms; autoreactive B cell; base; cell motility; chemokine; chemokine receptor; design; human CXCL13 protein; in vivo; islet; macrophage; migration; mouse model; novel; prevent; receptor; receptor expression; response; trafficking

DESCRIPTION (provided by applicant): Type I diabetes mellitus (T1DM) is a devastating disorder resulting from autoimmune destruction of insulin-producing pancreatic beta cells. TIDM is T cell mediated; B cells are also essential. Our long term goal is to elucidate the mechanisms by which B lymphocytes migrate to and are retained at sites of autoimmune attack and to use this information to design therapeutic options to disrupt those pathways and alter the pathological process. The specific hypothesis is that chemokines recruit B cells to pancreatic islets, where they contribute inflammatory signals driving benign insulitis to overwhelming disease. We base that hypothesis on the observations that: 1) we find large, well-organized B cell infiltrates in the islets, 2) an experimental technique which redistributes B cells away from islets is protective, 3) B cell receptor specificity (BCR) profoundly impacts disease as well as islet localization of B cells. The specific aims of this proposal are to: 1) identify the molecular signals that attract B lymphocytes to the islets of Non-Obese Diabetic mice and use this information to block B cell entry into the site of inflammation. We will investigate the effects of CXCL13 on B cell migration to the islets using transwell migration and adoptive transfer studies. In-vivo blockade of these signals to determine effects on native B cell localization and disease will follow. 2) Determine the effects of B cell specificity and activation status on entry into and retention in inflamed islets. We have engineered two NOD mouse lines expressing BCRs specific for insulin (disease-promoting), or a non-islet antigen (protective). We will compare the islet chemokine responses of naive, antigen-engaged, and T-cell-activated B cells from these mice using adoptive transfer, transwell migration, and confocal imaging. 3) Develop a mouse model of TIDM in which B cell chemoattraction is altered to further clarify the effects of B cell localization in this disease. These studies will identify the mechanims that mediate entry of B lymphocytes into a site of autoimmune attack and may identify novel targets of intervention in TIDM.

描述（由申请人提供）： I 型糖尿病 (T1DM) 是一种破坏性疾病，由产生胰岛素的胰腺 β 细胞的自身免疫性破坏引起。 TIDM 是 T 细胞介导的； B细胞也很重要。我们的长期目标是阐明 B 淋巴细胞迁移到并保留在自身免疫攻击部位的机制，并利用这些信息来设计治疗方案，以破坏这些途径并改变病理过程。具体的假设是趋化因子将 B 细胞募集到胰岛，在那里它们提供炎症信号，驱动良性胰岛炎发展为压倒性的疾病。我们的假设基于以下观察结果：1) 我们发现大的、组织良好的 B 细胞浸润在胰岛中，2) 将 B 细胞重新分配远离胰岛的实验技术具有保护作用，3) B 细胞受体特异性 (BCR) 深刻影响疾病以及 B 细胞的胰岛定位。该提案的具体目标是：1）识别将 B 淋巴细胞吸引到非肥胖糖尿病小鼠胰岛的分子信号，并利用该信息阻止 B 细胞进入炎症部位。我们将通过 Transwell 迁移和过继转移研究研究 CXCL13 对 B 细胞迁移至胰岛的影响。随后将体内阻断这些信号以确定对天然 B 细胞定位和疾病的影响。 2) 确定 B 细胞特异性和激活状态对进入和保留在发炎胰岛中的影响。我们设计了两种表达胰岛素特异性 BCR（促进疾病）或非胰岛抗原（保护性）的 NOD 小鼠品系。我们将使用过继转移、transwell 迁移和共聚焦成像来比较来自这些小鼠的初始 B 细胞、抗原结合细胞和 T 细胞激活 B 细胞的胰岛趋化因子反应。 3) 开发 TIDM 小鼠模型，其中 B 细胞化学吸引发生改变，以进一步阐明 B 细胞定位在该疾病中的作用。这些研究将确定介导 B 淋巴细胞进入自身免疫攻击部位的机制，并可能确定 TIDM 干预的新目标。