Highly differentiated IL5+ Th2 cells in food allergy and eosinophilic GI disease

嗜酸性胃肠道疾病（EGIDs）是一组以胃肠道嗜酸性炎症为特征的疾病。在过去的十年中，egid的发病率急剧增加，特别是嗜酸性粒细胞食管炎（EoE），但也有嗜酸性粒细胞胃肠炎（EG）。EGID患者通常有多种食物过敏，并且随着以氨基酸为基础的元素饮食的建立，疾病进入缓解期。总之，这表明EGID是一种食物过敏原驱动的嗜酸性炎症性肠道疾病。

Eosinophilic gastrointestinal disorders (EGIDs) are a group of diseases characterized by eosinophilic inflammation of the gastrointestinal tract. In the past decade, there has been a dramatic increase in the incidence of EGIDs, particularly eosinophilic esophagitis (EoE), but also eosinophilic gastroenteritis (EG). EGID patients often have numerous food hypersensitivities, and the disease goes into remission with the institution of an amino acid based elemental diet. In sum, this suggests that EGID is a food allergen driven eosinophilic inflammatory gut disease. Omalizumab is a humanized therapeutic anti-IgE monoclonal antibody. Anti-IgE therapy reduces the concentration of circulating free IgE, blocks IgE binding to both FcεRI and CD23, and down regulates surface FcεRI on mast cells, basophils and dendritic cells. Because of the multiple actions of anti-IgE therapy that affect antigen presenting cells (APCs), it has been postulated that by inhibiting APC function, anti-IgE therapy may have immunomodulatory activity on T cells. We hypothesized two distinct mechanisms whereby anti-IgE therapy could inhibit allergen specific Th2 responses. First, anti-IgE down regulates FcεRI on dendritic cells and blocks CD23 mediated allergen binding to APCs, thereby inhibiting IgE facilitated Ag capture by APCs, which in turn could result in decreased allergen specific T cell activation. Second, IgE signaling of anti-IgE inhibits mast cell and basophil activation in vivo, which may decrease IL-4 and/or TSLP expression, the lack of which could inhibit Th2 cell differentiation. To test this hypothesis, we assessed anti-IgE immunomodulation of allergen specific T cell responses during a clinical trial of omalizumab in subjects with allergic eosinophilic gastroenteritis. Four allergen specific T cell responses (maximal proliferation, proliferation dose response EC50, precursor frequency, and cytokine expression) were measured using carboxyfluorescein succinimidyl ester (CFSE) dye dilution and flow cytometry. There was no significant difference in allergen specific proliferation (CFSE dye dilution) between the pre-omalizumab baseline (10.0%) and the 16-week omalizumab time point (7.2%, p= 0.33). Anti-IgE therapy was associated with a small but significant left shift (opposite of the hypothesis) in the proliferative dose response to allergen, such that the EC50 at baseline was 1.5 times that of subjects on omalizumab. There was no significant difference in the precursor frequency of allergen specific T cells between the pre-omalizumab baseline (4.0 x 10e-4) and the 16 week omalizumab time point (6.5 x 10e-4, p= 0.33). No significant differences were found in the ratios of either IL-4:IFN-γ (baseline 0.81, omalizumab 0.63, p =0.15) or IL-5:IFN-γ (baseline 0.33, omalizumab 0.36, p=0.42) or of either Th2 cytokine to TNF-α. In contradistinction to the hypothesis, 16 weeks of anti-IgE therapy had no effect diminishing any index of allergen specific response. In sum, using multiple indices of T cell function, this study failed to demonstrate that anti-IgE therapy broadly or potently inhibits allergen specific T cell responses. As such, these data do not support a major role for IgE facilitated Ag presentation augmenting allergen specific T cell responses in vivo. Current work is underway to extend these findings to gut resident T cells in patients with eosinophilic GI disease. GI biopsies will be obtained and both flow cytometry and immunohistochemisty will be used to determine if a similar association with IL-5+ Th2 cells exists. Additional experiments will identify if there are other characteristics of food allergen specific Th2 cells in these disease states that may specifically contribute to anaphylactic vs. eosinophilic inflammatory food allergy.