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Regulation of T cell egress from inflamed skin

调节 T 细胞从发炎皮肤中排出

基本信息

批准号：
8477130
负责人：
Gudrun Philomena Debes
金额：
$ 32.5万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8477130
关键词：
Affect Animal Model Antibodies Antigens Apoptosis Arthritis Autoimmune Diseases Autoimmune Process Blood CCR6 gene CD8B1 gene CXCR4 gene Cells Chemotactic Factors Chronic Cutaneous Leishmaniasis Data Delayed Hypersensitivity Disease Down-Regulation Equilibrium Foundations Gene Targeting Goals Health Immune Immunologic Monitoring Infection Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Knowledge Left Lesion Lymph Lymphatic Endothelium Lymphocyte Lymphocytic Infiltrate Maintenance Mediating Memory Modeling Mus Nature Pain Peripheral Process Publishing Reagent Receptor Gene Recruitment Activity Regulation Relative (related person)Resolution Role Site Skin Specificity Supporting Cell T cell regulation T-Lymphocyte Testing Tissues base chemokine receptor fMet-Leu-Phe receptor inhibitor/antagonist migration novel receptor receptor expression screening sphingosine 1-phosphate

项目摘要

DESCRIPTION (provided by applicant): Lymphocytic tissue infiltrates in inflammatory and autoimmune diseases are the result of a dynamic balance of cell entry and exit, combined with localized proliferation and apoptosis. Whereas mechanisms of lymphocyte migration from the blood into tissues have been extensively studied and have proven to be key to the local inflammatory response, mechanisms responsible for T cell egress from extralymphoid tissues are only poorly defined. While it has been widely assumed that egress from tissues is a random process, we recently showed that lymphocyte exit from peripheral tissue is regulated and that CD4 and CD8 T cells require the expression of the chemokine receptor CCR7 for exit under non-inflammatory conditions. CCR7 and other "exit receptors" that promote T cell egress likely reduce localized lymphocyte accumulation, thereby affecting both immunosurveillance and inflammatory processes. As impaired tissue exit of inflammatory T cells could exacerbate local inflammation, exit receptors may serve as a novel target in the therapy of inflammatory diseases such as arthritis. Based on our extensive published and preliminary data, we hypothesize that T cell exit from inflamed peripheral tissues through the afferent lymph is controlled by both CCR7-dependent and -independent mechanisms, and that the relative importance of CCR7 and alternative exit receptors is determined by the nature and chronicity of the local inflammatory response. In this proposal, employing mouse and large animal models, we will test the role of CCR7 in T cell egress from inflamed skin as well as identify chemoattractant receptors mediating CCR7-independent T cell exit that operate under chronic inflammatory condition. Moreover, we propose to study the regulation of exit receptors on both bystander as well as antigen-specific memory/effector T cells recirculating through an inflammatory lesion. Importantly, using an established model of delayed type hypersensitivity, we will test the hypothesis that the regulated expression of tissue T cell CCR7 and other exit receptors modulate the initiation, maintenance and/or resolution of tissue inflammation. Moreover, we predict that the obtained results will serve as a proof of principle that targeting of T exit receptors can be used therapeutically to modulate the magnitude of inflammatory infiltrates in the treatment of autoimmune and inflammatory diseases.

描述(申请人提供)：炎症性和自身免疫性疾病中的淋巴细胞组织渗透是细胞进出的动态平衡以及局部增殖和凋亡的结果。虽然淋巴细胞从血液中迁移到组织中的机制已经被广泛研究，并被证明是局部炎症反应的关键，但导致T细胞从淋巴外组织中流出的机制还很少。虽然人们普遍认为外周组织的外流是一个随机的过程，但我们最近发现外周组织中的淋巴细胞外流是受调控的，在非炎症条件下，CD4和CD8T细胞需要趋化因子受体CCR7的表达才能外流。CCR7和其他促进T细胞外流的“出口受体”可能会减少局部的淋巴细胞聚集，从而影响免疫监测和炎症过程。由于受损的组织炎性T细胞出口可加重局部炎症，出口受体可能成为治疗关节炎等炎症性疾病的新靶点。基于我们广泛发表的和初步的数据，我们假设T细胞通过传入淋巴从炎症的外周组织中输出是由CCR7依赖和非依赖的机制控制的，并且CCR7和替代的退出受体的相对重要性由局部炎症反应的性质和慢性化决定。在这项提案中，我们将利用小鼠和大型动物模型，测试CCR7在炎症皮肤T细胞出口中的作用，并识别介导CCR7非依赖性T细胞出口的趋化受体，这些T细胞在慢性炎症条件下工作。此外，我们建议研究退出受体对旁观者和抗原特异性记忆/效应T细胞通过炎性病变循环的调节。重要的是，利用已建立的迟发性超敏反应模型，我们将检验组织T细胞CCR7和其他出口受体的调节表达调节组织炎症的启动、维持和/或消退的假设。此外，我们预测，所获得的结果将作为靶向T出口受体的原则的证据，该原则可用于治疗在治疗自身免疫性和炎症性疾病中调节炎症浸润物的大小。