Eosinophil Activities in Murine Models of Lung Diesease

描述(由申请人提供)：过敏性呼吸道病理的病因学讨论经常产生支持T细胞或嗜酸性粒细胞的支持者，每个人都声称他们的白细胞的重要性。然而，来自哮喘患者和过敏性呼吸道炎症小鼠模型的数据表明，除了细胞自主活动外，T细胞和嗜酸性粒细胞的相互作用可能对肺部病理的发生和发展比先前怀疑的更关键。这些研究明确表明，嗜酸性粒细胞和T淋巴细胞亚群通过直接的细胞-细胞相互作用和通过分泌炎症信号进行交流。总体而言，这些数据支持对肺中嗜酸性粒细胞活动的扩展看法，包括直接影响肺功能的免疫调节活动。我们使用无嗜酸性粒细胞小鼠(PHIL)、过敏原激发方案、哮喘转基因模型和过继细胞转移进行的研究都表明，嗜酸性粒细胞是激活和招募效应性T细胞到肺中所必需的。因此，嗜酸性粒细胞不是简单的对T细胞信号作出反应的破坏性效应细胞，而是在过敏原刺激后调节肺微环境中的免疫反应所必需的。建议的研究利用这些初步数据和我们新的嗜酸性粒细胞特异性小鼠模型和试剂/方法的可用性来检验中心假设，即嗜酸性粒细胞效应器功能具有两个独特的免疫调节作用，协调Th2驱动的呼吸道炎症。具体地说，我们假设嗜酸性粒细胞是(I)导致变应原特异性效应T细胞激活的次级免疫反应所必需的，(Ii)在过敏原刺激后将激活的T效应细胞重新招募到肺中是必需的。我们的目标是确定/描述嗜酸性粒细胞调节T细胞在肺中积累和激活的具体机制。该提案的目标将通过完成以下具体目标来实现：(1)确定肺嗜酸性粒细胞诱导Th2趋化因子在肺中表达的机制，并介导激活的过敏原特异性效应T细胞的募集；(2)证明在过敏原激发后，嗜酸性粒细胞介导的抗原提呈对于T细胞的激活是必需的；(3)确定嗜酸性粒细胞介导的T细胞的募集/激活对于促进与Th2驱动的肺部炎症相关的病理的重要性。公共卫生相关性：嗜酸性粒细胞是一种罕见的白细胞，其破坏性能力被认为会导致与过敏性哮喘相关的组织损伤。尽管如此，越来越多的文献表明，这种观点过于狭隘，嗜酸性粒细胞甚至可能调节肺部发生的免疫反应。事实上，我们对无嗜酸性粒细胞小鼠的使用和过继细胞转移使我们认为，嗜酸性粒细胞是激活/招募过敏原特异性T细胞所必需的，而后者反过来又促进呼吸道炎症。

DESCRIPTION (provided by applicant): Etiologic discussions of allergic respiratory pathologies frequently engender constituencies of pro-T cell or pro-eosinophil disciples each claiming the importance of their leukocyte. However, data from both asthma patients and mouse models of allergic respiratory inflammation suggest that in addition to cell autonomous activities, T cell and eosinophil interactions may be more critical to the onset and progression of pulmonary pathology than previously suspected. These studies specifically imply that eosinophils and T lymphocyte subpopulations communicate by both direct cell - cell interactions and through the secretion of inflammatory signals. Collectively, the data support an expanded view of eosinophil activities in the lung, including immunoregulative activities impinging directly on lung function. Our studies using eosinophil-less mice (PHIL), allergen provocation protocols, transgenic models of asthma, and adoptive cell transfer have each suggested that eosinophils are required for the activation and recruitment of effector T cells to the lung. Thus, instead of being simply destructive effector cells responsive to T cell-derived signals, eosinophils appear to be necessary for the regulation of immune responses in the pulmonary microenvironment following allergen provocation. The proposed studies capitalizes on these preliminary data and the availability of our novel eosinophil-specific mouse models and reagents/methodologies to test the central hypothesis that eosinophil effector functions have two unique immunoregulatory roles that orchestrate Th2-driven respiratory inflammation. Specifically, we hypothesize that eosinophils are (i) required for the secondary immune responses leading to the activation of allergen-specific effector T cells and are (ii) necessary for the recruitment of activated T effector cells to the lung following allergen provocation. Our goal is to identify/characterize the specific mechanisms by which eosinophils modulate the accumulation and activation of T cells in the lung. The objectives of the proposal will be achieved by the completion of the following Specific Aims: (1) To define mechanisms by which pulmonary eosinophils elicit Th2 chemokine expression in the lung and mediate the recruitment of activated allergen-specific effector T cells; (2) To demonstrate that eosinophil-mediated antigen presentation is required for T cell activation following allergen provocation; (3) To define the importance of eosinophil-mediated recruitment/activation of T cells as necessary to promote the pathologies associated with Th2-driven pulmonary inflammation. PUBLIC HEALTH RELEVANCE: Eosinophils are rare white blood cells whose destructive capabilities were assumed to cause the tissue damage associated with allergic asthma. Nonetheless, a growing literature suggests that this perspective is too narrow and that eosinophils may even regulate immune responses occurring in the lung. Indeed, our use of eosinophil-less mice and adoptive cell transfer has led us to suggest that eosinophils are required for the activation/recruitment of allergen-specific T cells that, in turn, promote respiratory inflammation.