Recent studies of asthma patients clearly demonstrate a diverse population based on symptoms and the character of inflammation displayed in clinical settings. Thus, in addition to allergic patients with eosinophilic airway inflammation that are generally controlled through corticosteroids, studies have identified growing populations of patients that are much more difficult to treat, including steroid refractory severe patients displaying both eosinophilic and neutrophilic inflammatory disease variants. This greater diversity of immune responses is mediated, in part, by allergen-specific T cell plasticity of pulmonary responses. Significantly, our concurrent studies in the mouse have suggested that eosinophils have under- appreciated roles in pathways necessary for immune regulation and the character of the inflammatory events occurring in the lung. This work originated with our early studies using eosinophil-deficient mice (PHIL), however, our more recent studies using a newly created inducible eosinophil-deficient mouse (iPHIL) have led us to suggest that eosinophil activities at the time of allergen challenge are linked to the diversity of T cell subtypes driving pulmonary inflammation (i.e., eosinophilic, neutrophilic, or mixed variants). The proposed studies capitalize on these preliminary data as well as our creation of a next generation mouse model (eoCRE) allowing eosinophil-specific gene knockouts and targeted gene overexpression. We will test the central hypothesis that eosinophil activities contribute to the character of alleric respiratory inflammation by (i) direct effects on neutrophil recruitment/accumulation in the lung and by (ii) modulating allergen-specific T cell subtype selection, polarizing responses to Th2 in the presence of eosinophils and Th17/Th1 in their absence. In the long term, our goal is to identify potential mechanisms that may explain the diversity of disease phenotypes in patients and confounding issues surrounding current therapies such as the use of corticosteroids and Mepolizumab. The objectives of this proposal will test our central hypothesis by the completion of the following Specific Aims: (1) To demonstrate that eosinophils directly suppress the level of allergen-induced airway neutrophils through the expression of anti-inflammatory lipids derived from 12/15- lipoxygenase activities; (2) To define the significance of eosinophil-derived IL-4 and TGF? expression as mechanisms modulating T cell subtypes leading to Th2 dominant vs. neutrophilic mixed Th2/Th17/Th1 immune responses; (3) To determine if steroid refractory neutrophilic subsets of allergic respiratory inflammation arise from eosinophil-ablating effects mediated by corticosteroids or as a combined consequence of targeting eosinophil and Th2 T cells.
Eosinophils are rare white blood cells with diverse activities whose importance is yet to be defined. Recent studies have highlighted the importance of this cell in immune responses occurring in the lung following allergen provocation. Indeed, our continued characterization of eosinophil-deficient mice and the development of new eosinophil targeted models/reagents have led us to propose that eosinophils directly contribute to the character of allergic immune responses and the inflammation displayed by the diverse group of asthma patients.
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