Eosinophil associated gastrointestinal diseases (EGID) are being increasingly recognized over the last decade. Despite the common finding of eosinophils in gastrointestinal (GI) specimens from a variety of patients, there has been only a limited understanding of the biological and pathological significance of eosinophils in the GI tract. Most studies on eosinophils in vivo have concentrated on trafficking and activation of these cells in the lung. However, over the last four years (during the initial period of funding for this grant), we have concentrated our efforts on analyzing the regulation and role of GI eosinophils at baseline and in allergic inflammatory states. Accordingly, we have developed several models of allergen or transgene induced eosinophil associated GI inflammation in mice. Several fundamental principles have emerged including the finding that eotaxin-1 provides an essential signal for regulating the baseline and allergen-induced homing of development of eosinophil-associated inflammation in the respiratory tract and the esophagus following specific aeroallergen or cytokine delivery to the lung. The current application is based on the central hypothesis that GI eosinophils (at baseline and following allergic triggers) are regulated by locally generated chemokines, eosinophil integrins, and Th2 cells. In particular, we aim to elucidate an integrative mechanism involving specific integrins (beta1,beta2, beta7), the eotaxin chemokines and their receptor CCR3, as well as Th2 cells and their products (e.g. IL-13), in the regulation of GI eosinophils.
The specific aims are designed to uncover the molecular and cellular mechanisms involved in regulating eosinophils at baseline (aim I), and following allergy-associated inflammatory triggers (aims II/III). Based on our preliminary studies and their clinical correlates, we will focus our attention on two GI segments (the esophagus and small intestine) with the aim of eventually comparing GI eosinophil responses in both segments. We will combine innovative experimental approaches (using unique experimental models and genetically altered mice) to dissect critical pathogenic mechanisms involved in experimental GI allergy. Given the apparently increasing incidence of EGID and the paucity of information currently available about GI eosinophils, we feel that these results are timely. Furthermore, these results will shed important insight into the potential utility of immune-based therapeutics (e.g. anti-cytokine agents) that are currently being developed for the treatment of asthma, that may also be beneficial for EGID.
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