Regulation of T cell migration by histamine
组胺调节 T 细胞迁移
基本信息
- 批准号:8212021
- 负责人:
- 金额:$ 37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-02-01 至 2013-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdoptive TransferAllergensAllergicAllergic inflammationAntigensAntihistaminesAsthmaAutoimmune ResponsesBindingBiological Response ModifiersBiologyCellsChemotactic FactorsChronic HepatitisCollaborationsCytoplasmic GranulesDelayed HypersensitivityDendritic CellsDevelopmentDiseaseGraft RejectionHealthHistamineHistamine ReceptorHistamine ReleaseHypersensitivityIgEImmigrationImmuneImmune responseImmunityIn VitroInfectionInflammationInflammatory ResponseInjuryInsulin-Dependent Diabetes MellitusInvestigationLinkLungLymphoidMediatingMediator of activation proteinModelingMusNamesNeuronal InjuryPrincipal InvestigatorProcessPropertyRecombinantsRecruitment ActivityRegulationResearchResearch PersonnelRestRoleSignal TransductionSkinSourceSystemT cell responseT-LymphocyteT-Lymphocyte SubsetsTestingTissuesWorkairway inflammationallergic airway diseaseallergic responseantigen challengebasecell motilitycell typechemokinechemokine receptorcookingcytokinein vivoinhibitor/antagonistmast cellmigrationneutrophilnovelpreventprogramsreceptorreconstitutionresponsetraffickingtumor
项目摘要
DESCRIPTION (provided by applicant): The recruitment of T lymphocytes into tissues is essential for local immune and inflammatory responses in both health and disease. The mechanisms that regulate T lymphocyte trafficking into tissues are not well characterized. Mast cells are constitutively resident in all tissues and are a rich source of preformed mediators. One of the most abundant mediators is histamine which is release upon mast cell activation by antigen- mediated activation or to insult. Despite being one of the most extensively studied molecules in biology, histamine has only recently been found to have several novel "immunoregulatory" properties and a fourth receptor was discovered in 2000. In addition, there is now growing evidence that other cell types are capable of synthesizing histamine, including dendritic cells and neutrophils.We have made the exciting finding that T cells that lack a specific receptor for histamine, H1R, fail to migrate into the lung upon allergen challenge. Mice lacking H1R also fail to develop allergic airway disease but respond normally to T cell derived mediators or when normal (H1R+) T cells are adoptively transferred. Treatment of wildtype mice with selective pharmacological inhibitors of H1R also reduced allergic airway responses. Based on our preliminary observations, we hypothesize that mast cell release of histamine promotes the recruitment of T cells into tissues and that the expression levels of H1R on T cells serves to regulate this. We predict these processes will be conserved across different tissues and that histamine serves as a ubiquitous regulator of T cell mediated inflammation and immunity. These concepts will be addressed by three specific aims using both in vivo and in vitro approaches: Specific Aim 1 will test the role of tissue-resident mast cells as a source of histamine and test their ability to recruit T lymphocytes in allergic airway disease. Specific Aim 2 will focus on the influence of H1R on T lymphocytes and will investigate the expression of H1R on subsets of T lymphocytes and the functional involvement of H1R in migration and transendothelial trafficking (in collaboration with Dr Joan Cook-Mills). Specific Aim 3 will investigate the involvement of histamine-driven T lymphocyte recruitment to the skin, using models of delayed-type hypersensitivity, and will test the hypothesis that histamine is a ubiqitous mechanism by which T lymphocytes are recruited into tissues.
描述(由申请人提供):T 淋巴细胞募集到组织中对于健康和疾病中的局部免疫和炎症反应至关重要。调节 T 淋巴细胞转运至组织的机制尚不明确。肥大细胞本质上存在于所有组织中,并且是预制介质的丰富来源。最丰富的介质之一是组胺,其在肥大细胞通过抗原介导的激活或损伤而激活时释放。尽管组胺是生物学中研究最广泛的分子之一,但直到最近才被发现具有多种新的“免疫调节”特性,并且在 2000 年发现了第四种受体。此外,现在越来越多的证据表明其他细胞类型能够合成组胺,包括树突状细胞和中性粒细胞。我们取得了令人兴奋的发现,缺乏组胺特异性受体 H1R 的 T 细胞无法迁移到 肺部受到过敏原挑战。缺乏 H1R 的小鼠也不会出现过敏性气道疾病,但对 T 细胞衍生介质或正常 (H1R+) T 细胞过继转移时反应正常。用选择性 H1R 药理学抑制剂治疗野生型小鼠也减少了过敏性气道反应。根据我们的初步观察,我们假设肥大细胞释放组胺促进 T 细胞募集到组织中,并且 T 细胞上 H1R 的表达水平可以对此进行调节。我们预测这些过程将在不同的组织中保守,并且组胺作为 T 细胞介导的炎症和免疫的普遍调节剂。这些概念将通过体内和体外方法通过三个具体目标来解决:具体目标 1 将测试组织驻留肥大细胞作为组胺来源的作用,并测试它们在过敏性气道疾病中招募 T 淋巴细胞的能力。具体目标 2 将重点关注 H1R 对 T 淋巴细胞的影响,并将研究 H1R 在 T 淋巴细胞亚群上的表达以及 H1R 在迁移和跨内皮运输中的功能参与(与 Joan Cook-Mills 博士合作)。具体目标 3 将使用迟发型超敏反应模型研究组胺驱动的 T 淋巴细胞募集到皮肤的参与情况,并将检验组胺是 T 淋巴细胞募集到组织中的普遍机制的假设。
项目成果
期刊论文数量(0)
专著数量(0)
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{{ truncateString('PAUL J BRYCE', 18)}}的其他基金
Regulation of food allergy and anaphylaxis by IL 33
IL 33 对食物过敏和过敏反应的调节
- 批准号:
8694990 - 财政年份:2014
- 资助金额:
$ 37万 - 项目类别:
Regulation of Food Allergy and Anaphylaxis by IL-33
IL-33 对食物过敏和过敏反应的调节
- 批准号:
8707087 - 财政年份:2013
- 资助金额:
$ 37万 - 项目类别:
Regulation and functions of mast cell-derived IL-33
肥大细胞来源的 IL-33 的调节和功能
- 批准号:
8308810 - 财政年份:2011
- 资助金额:
$ 37万 - 项目类别:
A novel murine model of food allergy to peanut or egg
对花生或鸡蛋食物过敏的新型小鼠模型
- 批准号:
7451159 - 财政年份:2008
- 资助金额:
$ 37万 - 项目类别:
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