The pulmonary eosinophilia accompanying the pathologies of asthma has been a correlative feature recognized even in the earliest studies investigating this disease. Innumerable investigations have confirmed and detailed this relationship, demonstrating that the presence of eosinophils is predictive of disease severity and occurs even in mild cases. The recruitment of eosinophils also occurs in animal models of allergen-mediated respiratory inflammation; the mouse, in particular, has been extensively studied. Despite the abundance of clinical studies and the availability of mouse models that correlate pulmonary eosinophilia with lung dysfunction, eosinophil effector functions are poorly understood and, indeed, questions remain as to the role(s), if any, of these leukocytes. We have created a novel line of mice genetically devoid of eosinophils. This ablation is accomplished through the specific expression of a suicide gene (i.e., Diphtheria Toxin A chain) exclusively in eosinophil-lineage committed cells of transgenic mice. The eosinophil ablation is absolute and specific as no effects are observed on other hematopoietically derived cells. This proposal utilizes our unique eosinophil-less line of mice, as well as other novel eosinophil-specific reagents/methodologies that we have developed, in two concurrent approaches testing the hypothesis that eosinophils have a causative role(s) in allergic airways disease (i.e., acute and chronic allergen-challenge protocols and genetic crosses with other established transgenic/gene knockout model systems). These objectives will be achieved by the completion of the following Specific Aims: (1) To determine unequivocally the contribution(s) of eosinophil effector functions to the pulmonary pathologies arising in an acute allergen sensitization/aerosol challenge model; (2) To define the role(s) of eosinophils in lung remodeling using a chronic model of allergen-mediated inflammation; (3) To define eosinophil-dependent mechanism(s) leading to late phase bronchoconstriction following allergen provocation; (4) To determine the contribution(s) of eosinophils to the previously characterized pulmonary pathologies of lung-expressing IL-5 transgenic mice.
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