Regulation of T cell egress from inflamed skin

调节 T 细胞从发炎皮肤中排出

• 批准号: 8074395
• 负责人: Gudrun Philomena Debes
• 金额: $ 34.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/8074395
• 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; Screening procedure; 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; sphingosine 1-phosphate

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. PUBLIC HEALTH RELEVANCE: Immune cells are the main cells responsible for tissue destruction and inflammation in arthritis and other chronic inflammatory diseases. Our goal is to determine the mechanisms by which immune cells leave inflamed tissues. Based on the new knowledge, therapies can be developed that force immune cells out of the tissue to stop ongoing inflammation and associated pain.

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以及局部增殖和凋亡的结果。尽管淋巴细胞从血液迁移到组织的机制已被广泛研究，并已被证明是局部炎症反应的关键，但负责 T 细胞从淋巴外组织流出的机制却知之甚少。虽然人们普遍认为组织的排出是一个随机过程，但我们最近发现淋巴细胞从外周组织的排出受到调节，并且 CD4 和 CD8 T 细胞需要趋化因子受体 CCR7 的表达才能在非炎症条件下排出。 CCR7 和其他促进 T 细胞流出的“退出受体”可能会减少局部淋巴细胞积聚，从而影响免疫监视和炎症过程。由于炎症 T 细胞的组织出口受损可能会加剧局部炎症，因此出口受体可能成为治疗关节炎等炎症性疾病的新靶点。根据我们广泛发表的初步数据，我们假设 T 细胞通过传入淋巴从发炎的外周组织退出是由 CCR7 依赖和独立机制控制的，并且 CCR7 和替代退出受体的相对重要性取决于局部炎症反应的性质和慢性性。在本提案中，我们将采用小鼠和大型动物模型来测试 CCR7 在 T 细胞从发炎皮肤排出中的作用，并鉴定在慢性炎症条件下介导不依赖 CCR7 的 T 细胞排出的趋化受体。此外，我们建议研究退出受体对旁观者以及通过炎症病变再循环的抗原特异性记忆/效应T细胞的调节。重要的是，使用已建立的迟发型超敏反应模型，我们将测试组织 T 细胞 CCR7 和其他退出受体的调节表达调节组织炎症的起始、维持和/或消退的假设。此外，我们预测所获得的结果将作为原理证明，即在自身免疫和炎症性疾病的治疗中，靶向T出口受体可用于调节炎症浸润的程度。公共卫生相关性：免疫细胞是造成关节炎和其他慢性炎症性疾病的组织破坏和炎症的主要细胞。我们的目标是确定免疫细胞离开发炎组织的机制。基于新知识，可以开发出迫使免疫细胞离开组织的疗法，以阻止持续的炎症和相关疼痛。