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:8265297
- 负责人:
- 金额:$ 34.21万
- 依托单位:
- 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:
- 关键词:AffectAnimal ModelAntibodiesAntigensApoptosisArthritisAutoimmune DiseasesAutoimmune ProcessBloodCCR6 geneCD8B1 geneCXCR4 geneCellsChemotactic FactorsChronicCutaneous LeishmaniasisDataDelayed HypersensitivityDiseaseDown-RegulationEquilibriumFoundationsGene TargetingGoalsHealthImmuneImmunologic MonitoringInfectionInflammationInflammatoryInflammatory InfiltrateInflammatory ResponseKnowledgeLeftLesionLymphLymphatic EndotheliumLymphocyteLymphocytic InfiltrateMaintenanceMediatingMemoryModelingMusNaturePainPeripheralProcessPublishingReagentReceptor GeneRecruitment ActivityRegulationRelative (related person)ResolutionRoleScreening procedureSiteSkinSpecificitySupporting CellT cell regulationT-LymphocyteTestingTissuesbasechemokine receptorfMet-Leu-Phe receptorinhibitor/antagonistmigrationnovelreceptorreceptor expressionsphingosine 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. 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):炎性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中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细胞从淋巴外组织中流出的机制却定义不清。虽然人们普遍认为从组织中排出是一个随机的过程,但我们最近发现淋巴细胞从外周组织中的排出是受调节的,并且CD 4和CD 8 T细胞需要表达趋化因子受体CCR 7才能在非炎症条件下排出。CCR 7和其他促进T细胞排出的“出口受体”可能减少局部淋巴细胞积聚,从而影响免疫监视和炎症过程。由于炎性T细胞的受损组织出口可加剧局部炎症,出口受体可作为治疗炎性疾病如关节炎的新靶点。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发炎的外周组织中退出是由CCR 7依赖性和非依赖性机制控制的,并且CCR 7和替代退出受体的相对重要性由局部炎症反应的性质和慢性性决定。在这项提案中,采用小鼠和大型动物模型,我们将测试CCR 7在T细胞从发炎皮肤中排出的作用,并确定介导CCR 7独立T细胞退出的化学引诱物受体,这些受体在慢性炎症条件下起作用。此外,我们建议研究退出受体对旁观者以及抗原特异性记忆/效应T细胞通过炎症病变再循环的调节。重要的是,使用已建立的迟发型超敏反应模型,我们将检验组织T细胞CCR 7和其他出口受体的调节表达调节组织炎症的起始、维持和/或消退的假设。此外,我们预测,所获得的结果将作为一个原则的证明,靶向T出口受体可以用于治疗调节炎症浸润的程度,在治疗自身免疫性和炎症性疾病。公共卫生关系:免疫细胞是关节炎和其他慢性炎症性疾病中负责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。基于新的知识,可以开发出迫使免疫细胞离开组织的疗法,以阻止正在进行的炎症和相关疼痛。
项目成果
期刊论文数量(0)
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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
- 批准号:
7729318 - 财政年份:2009
- 资助金额:
$ 34.21万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 34.21万 - 项目类别:
Regulation of T cell egress from inflamed skin
调节 T 细胞从发炎皮肤中排出
- 批准号:
7869373 - 财政年份:2009
- 资助金额:
$ 34.21万 - 项目类别:
Regulation of T cell egress from inflamed skin
调节 T 细胞从发炎皮肤中排出
- 批准号:
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