Microbiota regulation of intestinal eosinophils

摘要 食物过敏的特征是对无害的食物抗原的异常免疫激活，并影响 占美国人口的5%-8%。目前的护理标准仍然局限于避免过敏原，这表明 需要新的治疗途径。一种有希望的方法是控制过敏的开始 辅助性T细胞(Th2)介导的炎症反应。在食物过敏中，Th2细胞是由抗原- 在肠道中呈递树突状细胞(DC)，然后由肠道嗜酸性粒细胞激活，这是一种先天免疫 与2型免疫相关的细胞类型。因此，对肠道嗜酸性粒细胞的调节是一个很有前途的研究方向。 在过敏反应开始时进行干预的时间点。尽管肠子里含有最大的 体内嗜酸性粒细胞数量，了解控制其积累和功能的信号 仍然是有限的。一个可能调节肠道嗜酸性粒细胞的环境信号是微生物区系，这是至关重要的。 在塑造肠道免疫细胞方面。有趣的是，无论是在无菌(GF)小鼠中还是在 在小鼠和人类中，抗生素治疗也与病情恶化和发病率增加有关。 食物过敏，但其机制尚不完全清楚。我假设微生物区系调节肠道 嗜酸性粒细胞及其在食物过敏中的作用。我提出的肠道嗜酸性粒细胞调节机制研究 由微生物群最终将花生抗原食物过敏模型确定如何环境 因子在疾病中控制嗜酸性粒细胞的功能。阐明肠道特异信号如何影响嗜酸性粒细胞 提高对它们生物学的了解，并确定这些细胞在食物过敏中的新治疗靶点。 此外，与本研究计划一起制定的培训计划将为我提供一份蓝图，为我做好准备 成功的学术生涯。在我的赞助商和共同赞助商的支持下， 在哈佛大学的协作环境下，这份奖学金将使我能够为最终独立做好准备 在黏膜免疫学方面的地位。

Abstract Food allergy is characterized by aberrant immune activation in response to an innocuous food antigen and affects 5-8% of the US population. The current standard of care remains limited to allergen avoidance, demonstrating the need for new therapeutic avenues. One promising approach would be to control the initiation of the allergic inflammatory response mediated by T helper 2 (Th2) cells. In food allergy, Th2 cells are induced by antigen- presenting dendritic cells (DCs) in the gut, which in turn are activated by intestinal eosinophils, an innate immune cell type associated with type 2 immunity. Therefore, regulation of intestinal eosinophils represents a promising point at which to intervene at the beginning of an allergic response. Although the gut contains the largest eosinophil population in the body, understanding of the signals controlling their accumulation and function remains limited. An environmental signal likely to regulate intestinal eosinophils is the microbiota, which is critical in shaping intestinal immune cells. Interestingly, microbiota disruption either in germ-free (GF) mice or with antibiotic treatment in both mice and humans is also associated with exacerbation and increased incidence of food allergy, but the mechanism is not entirely clear. I hypothesize that the microbiota regulates intestinal eosinophils and their function in food allergy. My proposed mechanistic studies of intestinal eosinophil regulation by the microbiota will culminate in a peanut antigen food allergy model to determine how this environmental factor controls eosinophil function in disease. Elucidating how gut-specific signals influence eosinophils would improve understanding of their biology and identify novel therapeutic targets for these cells in food allergy. Additionally, the Training Plan developed alongside this Research Plan will provide a blueprint to prepare me for a successful academic career. With the support of my Sponsor and Co-Sponsor in the innovative and collaborative environment at Harvard, this fellowship will enable me to be well poised for an eventual independent position in mucosal immunology.