MECHANISMS THAT REGULATE TH2-MEDIATED LUNG INFLAMMATION

TH2 介导的肺部炎症的调节机制

• 批准号: 7448476
• 负责人: KEVAN ROBERTS
• 金额: $ 29.72万
• 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/7448476
• 关键词: Address; Allergens; Allergic; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Asthma; Attenuated; Automobile Driving; Breathing; CD4 Positive T Lymphocytes; Cells; Chronic; Data; Defect; Development; Disease; Epoprostenol; Epoprostenol Receptors; Event; Extrinsic asthma; Figs - dietary; Glucocorticoids; Goals; IL2RA gene; Immune; Inflammation; Inflammatory; Inflammatory Response; Interleukin 4 Receptor; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Lung; Lung Inflammation; Mediating; Messenger RNA; Molecular; Mucositis; Mucous Membrane; Pharmaceutical Preparations; Play; Pneumonia; Prevalence; Process; Production; Property; Prostaglandins; Reaction; Regulation; Research Personnel; Role; Site; Staging; Stimulus; T-Lymphocyte; Th2 Cells; Tumor Necrosis Factor Receptor; Western World; Work; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; base; cyclooxygenase 2; cytokine; immunoregulation; in vivo; novel therapeutics; progesterone 11-hemisuccinate-(2-iodohistamine); programs; receptor; research study; response

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(申请人提供)：过敏性哮喘的特征是由CD4+Th2细胞介导的呼吸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的缺陷而产生的。我们的长期目标是阐明哪些免疫调节事件通常可用于限制由CD4+T细胞介导的过敏性呼吸道炎症。我们的工作使我们能够提出这样的中心假设：“过敏性肺部炎症是由PGI2和CD4+CD25+调节性T细胞的作用调节的，它们共同作用于抑制肺粘膜Th2反应。”我们基于这一假设的研究表明，体内选择性抑制COX-2特异性地减少了PGI2的产生，并导致伴随而来的过敏性炎症水平的增加。PGI2受体(IP受体)由IL-4诱导，主要由CD4+CD25+T调节细胞表达。研究表明，CD4+CD25+T细胞在调节Th2介导的肺部炎症中起重要作用。3将调查与控制过敏性炎症的关键调控机制有关的目标。1.阐明抗炎前列腺素I2产生的细胞和分子条件，探讨其受体在肺部炎症过程中的诱导和功能。2.探讨CD4+CD25+T调节细胞抑制变态反应性肺部炎症的机制及IL-10和糖皮质激素诱导的肿瘤坏死因子受体在其中的作用。本课程将讨论CD4+CD25+T细胞在体内抑制(I)CD4+Th2反应的发展和(Ii)效应Th2介导的炎症反应中的作用。3.阐明PGI2和CD25+T细胞协同抑制变态反应性炎症的机制，以及这种免疫调节在NSAID诱导的哮喘加重中的作用。