MECHANISMS THAT REGULATE TH2-MEDIATED LUNG INFLAMMATION

TH2 介导的肺部炎症的调节机制

• 批准号: 7091675
• 负责人: KEVAN ROBERTS
• 金额: $ 30.61万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-05 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091675
• 关键词: asthma; cytokine receptors; gene targeting; genetically modified animals; helper T lymphocyte; hypersensitivity; immunomodulators; inflammation; interleukin 10; laboratory mouse; prostaglandin receptor; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Allergic asthma is characterized by airway hyperreactivity and chronic mucosal inflammation mediated by CD4+ Th2 cells. There is increasing evidence to suggest that the chronic inflammation arises as a consequence of a defect in regulatory mechanisms. Our long-term goal is to elucidate which immunomodulatory events are normally operative to limit allergic airway inflammation mediated by CD4+ T cells. Our work has enabled us to formulate the central hypothesis that "allergic pulmonary inflammation is regulated by the action of PGI2 and CD4+CD25+ regulatory T cells, which cooperate in the suppression of lung mucosal Th2 responses". We base this hypothesis from studies demonstrating that selective inhibition of COX-2 in vivo specifically reduced PGI2 production and resulted in a concomitant increase in the level of allergic inflammation. The PGI2 receptor (IP-receptor) was induced by IL-4 and predominantly expressed by CD4+CD25+ T regulatory cells. CD4+CD25+ T cells were shown to play a crucial role in regulating Th2-mediated pulmonary inflammation. 3 aims pertaining to key regulatory mechanisms that control allergic inflammation will be investigated. 1. To elucidate the cellular and molecular requirements for the production of the anti-inflammatory prostanoid PGI2 and examine the induction and function of its receptor during lung inflammation. 2. To determine the mechanism by which CD4+CD25+ T regulatory cells suppress allergic pulmonary inflammation and the role of IL-10 and glucocorticoid-induced TNF receptor in modulating this regulation. The role of CD4+CD25+ T cells in suppressing (i) the development of CD4+ Th2 responses, and (ii) effector Th2-mediated inflammatory responses in vivo will be addressed. 3. To resolve the mechanism by which PGI2 and CD25+ T cells cooperate to limit allergic inflammation and the contribution of this form of immune modulation to NSAID-induced exacerbations of asthma.

描述（由申请人提供）：过敏性哮喘的特征是由CD 4 + Th 2细胞介导的气道高反应性和慢性粘膜炎症。越来越多的证据表明，慢性炎症是由于调节机制缺陷引起的。我们的长期目标是阐明哪些免疫调节事件通常可以限制CD 4 + T细胞介导的过敏性气道炎症。我们的工作使我们能够制定的核心假设，即“过敏性肺部炎症是由PGI 2和CD 4 + CD 25+调节性T细胞，这在肺粘膜的Th 2反应的抑制合作的行动进行调节”。我们的研究表明，选择性抑制考克斯-2在体内特异性地减少PGI 2的生产，并导致过敏性炎症水平的伴随增加。PGI 2受体（IP-受体）由IL-4诱导并主要由CD 4 + CD 25 + T调节细胞表达。CD 4 + CD 25 + T细胞在调节Th 2介导的肺部炎症中起关键作用。将研究与控制过敏性炎症的关键调节机制有关的3个目标。1.阐明产生抗炎前列腺素PGI 2的细胞和分子要求，并检查其受体在肺部炎症中的诱导和功能。2.目的探讨CD 4 + CD 25+调节性T细胞抑制变应性肺炎的机制及IL-10和糖皮质激素诱导的TNF受体在调节这种调节中的作用。CD 4 + CD 25 + T细胞在体内抑制（i）CD 4 + Th 2应答的发展和（ii）效应Th 2介导的炎症应答中的作用将得到解决。3.研究PGI 2和CD 25 + T细胞协同限制过敏性炎症的机制，以及这种免疫调节对NSAID诱导的哮喘加重的作用。