Allergic inflammation and resulting disease caused by inappropriate responses to food and environmental antigens is a growing public health issue. Allergic inflammation is associated with T helper 2 (Th2) CD4+ T cells that produce Th2 cytokines, including interleukin-4 (IL-4) and IL-13. While the role of Th2 CD4+ T cells is well recognized during allergic responses, the innate cell types and cytokines that initiate and regulate allergic inflammation remain poorly defined. Recent studies have implicated basophils as an innate cell that promotes Th2 cytokine responses. Additionally, the cytokine thymic stromal lymphopoietin (TSLP) has been associated with the development of allergic disease in mice and human patients. Preliminary data described in this proposal show that TSLP elicits a unique population of murine basophils that are responsive to the Th2- associated cytokine IL-33. Additional data demonstrate that activated human basophils express the TSLP receptor (TSLPR), and that basophils isolated from patients suffering from eosinophilic esophagitis (EoE) are more likely to express the IL-33R. Taken together, these data suggest that TSLP may regulate human basophil responses that influence allergic inflammation.
The Specific Aims outlined in this proposal will directly test the influence of TSLP on human basophil populations.
Aim 1 will utilize a humanized mouse model in which human basophils can be readily defined to assess human basophil phenotype and function following exposure to TSLP in vitro and in vivo. Additionally, a novel murine food allergy model will be used to investigate the effects of TSLP on human basophil populations in humanized mice during the development of allergic inflammation in the intestine. Studies described in Aim 2 will assess basophil phenotype and function in the peripheral blood and esophageal tissue of human EoE patients and healthy controls and basophil responsiveness to TSLP and IL-33 in vitro. Finally, basophil responses in patients that have a gain- or loss-of function mutation in the TSLP gene will be assessed and correlated to disease severity to determine whether TSLP genotype, basophil phenotype and function, and allergic disease state are associated. Collectively, these studies will utilize novel models and approaches, in conjunction with cutting-edge studies in human patients, to investigate the innate mechanisms that control allergic inflammation in humans.
Asthma and allergic diseases cause significant morbidity and mortality in industrialized nations, with more than 50% of people in the US suffering from at least one allergic disease. As the prevalence of allergic diseases continues to grow, there is a need to better understand the biological mechanisms that lead to allergic inflammation, in order to develop therapeutics and management strategies. This proposal will investigate the specific immunological pathways that underlie allergic disease in human patients.
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