MECHANISMS THAT REGULATE TH2-MEDIATED LUNG INFLAMMATION

描述（由申请人提供）：过敏性哮喘以气道高反应性和慢性黏膜炎症为特征，由CD4+ Th2细胞介导。越来越多的证据表明，慢性炎症是调节机制缺陷的结果。我们的长期目标是阐明哪些免疫调节事件通常是有效的，以限制由CD4+ T细胞介导的过敏性气道炎症。我们的工作使我们能够提出“变应性肺部炎症是由PGI2和CD4+CD25+调节性T细胞的作用调节的，它们共同抑制肺粘膜Th2反应”的中心假设。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，并导致过敏性炎症水平的增加。PGI2受体（ip受体）受IL-4诱导，主要由CD4+CD25+ T调节性细胞表达。CD4+CD25+ T细胞在调节th2介导的肺部炎症中发挥关键作用。将研究与控制过敏性炎症的关键调控机制有关的3个目标。1. 目的：阐明抗炎前列腺素PGI2在肺炎症过程中产生的细胞和分子要求，并研究其受体的诱导和功能。2. 探讨CD4+CD25+ T调节性细胞抑制变应性肺部炎症的机制以及IL-10和糖皮质激素诱导的TNF受体在这一调节中的作用。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将被解决。3. 解决PGI2和CD25+ T细胞合作限制过敏性炎症的机制，以及这种形式的免疫调节对非甾体抗炎药诱导的哮喘加重的贡献。

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.