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（由申请人提供）：炎症和自身免疫性疾病中的淋巴细胞组织浸润是细胞进入和退出的动态平衡的结果，并结合了局部增殖和凋亡。尽管已经对淋巴细胞迁移到组织的迁移的机制进行了广泛的研究，并已证明是局部炎症反应的关键，但导致T细胞出口的机制仅定义不明。尽管已广泛认为从组织中出口是一个随机过程，但我们最近表明，调节了从周围组织中退出淋巴细胞，并且CD4和CD8 T细胞需要在非炎症条件下表达趋化因子受体CCR7的表达。 CCR7和其他促进T细胞出口的“退出受体”可能会减少局部淋巴细胞的积累，从而影响免疫监视和炎症过程。由于炎症性T细胞的组织出口受损可能会加剧局部炎症，因此出口受体可以作为治疗炎性疾病（如关节炎）的新靶标。根据我们广泛的发布和初步数据，我们假设通过传入淋巴从发炎的外周组织退出的T细胞受CCR7依赖性和独立的机制控制，并且CCR7的相对重要性和替代出口受体的相对重要性是由局部炎症反应的性质和慢性。在该提案中，采用小鼠和大动物模型，我们将测试CCR7在发炎皮肤中的T细胞出口中的作用，并鉴定介导在慢性炎症状态下运行的CCR7独立的T细胞出口的趋化受体受体。此外，我们建议研究旁观者以及抗原特异性记忆/效应的T细胞对通过炎症病变循环的调节。重要的是，使用已建立的延迟类型过敏的模型，我们将检验以下假设：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起始，维持和/或分辨率。此外，我们预测，获得的结果将证明可以用治疗靶向T出口受体来调节自身免疫性和炎症性疾病的治疗时调节炎症性浸润的大小。