Dissecting mechanisms underlying the pathogenesis of eosinophilic esophagitis (HYP6P.263)

Eosinophilic esophagitis (EoE) is an allergic disease characterized by esophageal eosinophilia, inflammation, and dysfunction. EoE has become increasingly common, but current management strategies are nonspecific. Thus, there is an urgent need to identify new pathways that could be targeted to treat EoE. Recently, EoE was associated with a gain-of-function polymorphism in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation and peripheral basophilia. However, how TSLP and basophils might contribute to the development of eosinophil responses during EoE remains unknown. Here, we employed a new murine model of EoE-like disease to investigate the role of TSLP and basophils in promoting esophageal eosinophil responses. Development of esophageal eosinophil responses was dependent on TSLP-elicited basophils, and antibody-mediated neutralization of TSLP or depletion of basophils ameliorated established esophageal eosinophilia. In addition, we examined how sort-purified human basophils influence eosinophil responses in vitro. Finally, elevated TSLP levels and exaggerated basophil responses observed in esophageal biopsies from EoE patients correlated with eosinophil responses. Together, these data indicate that TSLP-elicited basophil responses may play a key role in mediating eosinophil responses in EoE, suggesting that the TSLP-basophil axis could represent a new and promising therapeutic target to treat this disease.