Lymphocyte Migration in Development of Type 1 Diabetes

1 型糖尿病发展过程中的淋巴细胞迁移

• 批准号: 6866932
• 负责人: SARA A MICHIE
• 金额: $ 28.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866932
• 关键词: NOD mouse; T lymphocyte; autoimmune disorder; cell adhesion molecules; cell migration; chemokine; chemokine receptor; flow cytometry; immune tolerance /unresponsiveness; immunologic assay /test; immunologic memory; immunopathology; inflammation; insulin dependent diabetes mellitus; laboratory rat; lymph nodes; pancreas; pancreatic islets; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): OBJECTIVES Type 1 diabetes (T1DM) is a T cell mediated autoimmune disease. In the early stages of the autoimmune response, naive autoreactive T cells migrate from blood into pancreatic lymph nodes where they meet Beta cell antigens; memory/effector offspring of these T cells then migrate from blood into islets to initiate the inflammation that leads to Beta cell destruction. The migration of lymphocytes from blood into tissues requires tissue-selective multistep cascades with sequential lymphocyte/endothelial adhesion and activation steps. Our goals are to identify the endothelial adhesion and activating molecules (such as chemokines) that are expressed in pancreatic lymph nodes and islets in the early stages of inflammation, to define the roles of these molecules in lymphocyte recruitment to these sites and in the initiation of the autoimmune response, and to determine which molecules are therapeutic targets for the prevention of T1DM. RESEARCH PLANS AND METHODS We will use tissue section immunohistology, suspension immunofluorescence staining with flow cytometry, and laser capture microdissection (LCM) with RT-PCR to determine which adhesion molecules, chemokines, and chemokine receptors are present in pancreatic lymph nodes (Aim 1) and islets (Aim 2) of nonobese diabetic (NOD) mice in the early stages of the autoimmune process. The physiologic roles of these molecules in the migration of naive autoreactive T cells into pancreatic lymph nodes (Aim 1) and in the production of memory/effector T cells which migrate to islets (Aim 2) will be defined using in vivo lymphocyte migration assays. In Aim 3, we will work closely with Dr. Hugh McDevitt to determine the effects of TNFalpha and anti- TNFalpha on lymphocyte migration pathways and on the development of autoimmunity or tolerance.

描述（由申请人提供）： 目标 1 型糖尿病 (T1DM) 是一种 T 细胞介导的自身免疫性疾病。在自身免疫反应的早期阶段，初始自身反应性 T 细胞从血液迁移到胰腺淋巴结，在那里它们遇到 β 细胞抗原；然后，这些 T 细胞的记忆/效应子代从血液迁移到胰岛，引发炎症，导致 β 细胞破坏。淋巴细胞从血液迁移到组织中需要组织选择性多步级联，其中包括顺序的淋巴细胞/内皮粘附和激活步骤。我们的目标是鉴定炎症早期阶段在胰腺淋巴结和胰岛中表达的内皮粘附和激活分子（例如趋化因子），确定这些分子在淋巴细胞募集到这些部位和启动自身免疫反应中的作用，并确定哪些分子是预防炎症的治疗靶点。 T1DM。 研究计划和方法 我们将使用组织切片免疫组织学、流式细胞术悬浮免疫荧光染色以及 RT-PCR 激光捕获显微切割 (LCM) 来确定非肥胖糖尿病 (NOD) 小鼠早期阶段的胰腺淋巴结（目标 1）和胰岛（目标 2）中存在哪些粘附分子、趋化因子和趋化因子受体。 自身免疫过程。这些分子在初始自身反应性 T 细胞迁移到胰腺淋巴结（目标 1）和迁移到胰岛的记忆/效应 T 细胞（目标 2）的产生中的生理作用将使用体内淋巴细胞迁移测定来确定。在目标 3 中，我们将与 Hugh McDevitt 博士密切合作，以确定 TNFα 和抗 TNFα 对淋巴细胞迁移途径以及自身免疫或耐受性发展的影响。