Eosinophilic gastrointestinal disorders (EGIDs) are a group of diseases characterized by eosinophilic inflammation of the gastrointestinal tract. In the past 20 years, there has been a dramatic increase in the incidence of EGIDs, particularly eosinophilic esophagitis (EoE), but also eosinophilic gastroenteritis (EGE). EGID patients often have numerous food hypersensitivities, and the disease goes into remission with the institution of an amino acid based allergen-free elemental diet. In sum, this suggests that EGID is a food allergen driven eosinophilic inflammatory gut disease. In our previous work, we have demonstrated that IL-5+ Th2 cells are associated with EGID (eosinophilic food allergy), but not anaphylactic forms of food allergy. We have further characterized these IL-5+ Th2 cells as more highly differentiated Th2 cells that are the product of multiple rounds of antigenic stimulus. In sum, these findings suggest that food allergen-driven IL-5+ Th2 cells are the major pathway driving eosinophilic gut inflammation in EGID. To facilitate both functional studies as well as their identification in tissue samples, we have developed phenotypic markers for these IL-5+ Th2 cells. These markers identify an IL-5 bright CD4 T cell population. In both EGID and atopic dermatitis, the frequency of these IL-5+ Th2 cells is tightly correlated to peripheral blood eosinophil count, suggesting that this cell population is driving blood eosinophilia. Additionally, we have shown that IL-5+ Th2 express gut tissue homing receptors and home to gut tissue in EGID. In a variety of assay systems, IL-5+ Th2 cells have greater functional activity than IL-5- Th2 cells. This indicates that the IL-5+ subpopulation is the major Th2 population driving allergic eosinophilic inflammation. We have also shown that Th2 cells, and in particular IL-5+ Th2 cells, are highly sensitive to molecular target of rapamycin (mTOR) inhibitors, such as rapamycin and Torin 1. Rapamycin inhibition of proliferation is significantly greater for IL-5+ Th2 vs. either IL-5- Th2 or Th1 cells, at concentrations ranging from 0.25-10 nM. IL-5+ Th2 cells demonstrated enhanced S6 ribosomal protein phosphorylation, indicating that the mTORC1 pathway is preferentially activated in this subpopulation. The key role of the mTORC1 pathway in IL-5+ Th2 cell proliferation was confirmed using RNA inhibition of mTORC1 pathway genes. These results demonstrate that IL-5+ Th2 cells are highly metabolically active and as such have upregulated the mTORC1 pathway. This mTORC1 upregulation by IL-5+ Th2 cells results in their greater sensitivity to mTOR inhibitors. These findings suggest that mTOR inhibitors may have relative specificity in treating allergic eosinophilic inflammatory diseases. To test this hypothesis we have begun protocol 13-I-0094, a Phase I Open-Label Study of Sirolimus in Eosinophil-Associated Gastrointestinal Disorders. Retinoic acid (RA) is the major form of vitamin A that is active in the body and is critical to mounting a healthy immune response. We examined the mechanism by which RA promotes Th2 responses. In this work we demonstrate that RA enhances the output of Th2 cells from allergen driven cultures and that most of this effect was limited to the IL-5+ Th2 subpopulation. Conversely, the RA receptor alpha antagonist Ro415253 inhibited IL-5+ Th2 cell proliferation. This increased output of IL-5+ Th2 cells was due to enhanced proliferation. Similarly, IL-5 gene expression was augmented by RA and reciprocally inhibited by Ro415253. These results suggest that RA receptor antagonism is a potential means to therapeutically target allergic inflammation. Conversely, these data suggest that RA supplementation may potentially enhance allergic inflammation.
Showing the most recent 10 out of 12 publications
