Eosinophil Activities in Murine Models of Lung Diesease

点击翻译按钮获取中文摘要

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.