B Cell Traffic in Type I Diabetes Mellitus

描述（由申请人提供）： I型糖尿病（T1 DM）是由产生胰岛素的胰腺β细胞的自身免疫性破坏引起的破坏性疾病。TIDM是T细胞介导的; B细胞也是必需的。我们的长期目标是阐明B淋巴细胞迁移和保留在自身免疫性攻击位点的机制，并利用这些信息设计治疗方案来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，将良性胰岛炎驱动为压倒性疾病。我们的假设基于以下观察结果：1）我们发现胰岛中存在大的、组织良好的B细胞浸润，2）将B细胞从胰岛中重新分布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。该提议的具体目的是：1）鉴定吸引B淋巴细胞至非肥胖糖尿病小鼠的胰岛的分子信号，并使用该信息来阻断B细胞进入炎症部位。我们将使用transwell迁移和过继转移研究来研究CXCL 13对B细胞向胰岛迁移的影响。随后将进行这些信号的体内阻断以确定对天然B细胞定位和疾病的影响。2)确定B细胞特异性和活化状态对进入和保留在发炎胰岛中的影响。我们设计了两个NOD小鼠系，表达对胰岛素（促进疾病）或非胰岛抗原（保护性）特异性的BCR。我们将使用过继转移、transwell迁移和共聚焦成像来比较这些小鼠的幼稚、抗原结合和T细胞激活的B细胞的胰岛趋化因子应答。3)开发TIDM小鼠模型，其中B细胞化学吸引力改变，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干预的新靶点。

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.