Eosinophil accumulation in the gastrointestinal tract occurs in numerous diseases (i.e. food allergy, eosinophilic gastroenteritis, allergic colitis, and gastroesophageal reflex). Some of these disorders are highly prevalent and clinically important. For example, food allergy has been documented in 2-4% of children and can by life threatening. Despite the common finding of eosinophils in tissue specimens from these patients, and increasing evidence that these cells have a pathogenic role in these disorders, there has been only a limited understanding of the biological and pathological significance of eosinophils in the gastrointestinal tract. We have begun to elucidate the mechanisms of eosinophil trafficking into the gastrointestinal tract and have developed a novel model of food allergen-induced gastrointestinal inflammation. This grant application proposes to elucidate the cellular and molecular mechanisms involved in regulating eosinophil trafficking into the gastrointestinal tract. The application is based on the main hypothesis that eosinophils normally reside in the gastrointestinal tract and that their homing into this organ is regulated by locally generated eotaxin, a CC chemokine with eosinophil selective activity, that works cooperatively with interleukin (IL)-5. The regulation of gastrointestinal eosinophils by these two cytokines and T cells will be evaluated in healthy states, following oral allergen challenge in the model of allergen-induced gastrointestinal inflammation, and by transgenic over-expression of these cytokines specifically in the intestine.
Four aims will be undertaken: (I) the mechanisms of eosinophil homing into the gastrointestinal tract during health states; (ii) characterization of the early and late phase response in the gastrointestinal tract during allergic inflammation; (iii) the mechanism of eosinophil trafficking into the gastrointestinal tract during allergic inflammation; and (IV) the consequences of transgenic expression of eotaxin and IL-5 in the intestine. The proposed experiments will define the mechanisms that regulate gastrointestinal eosinophils at baseline and following acute (allergic) and chronic (transgenic) inflammatory stimuli in the gastrointestinal tract. These basic studies will hopefully provide a better understanding of physiological processes in the gastrointestinal tract and diseases processes such as food allergy which may be related, at least in part, to dysregulation of eosinophil trafficking.
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