Food Allergy and Goblet Cell Antigen Passages

 描述(申请人提供)：食物过敏在美国是一种严重而常见的疾病，被认为影响到每四个家庭中就有一个。已批准的食物过敏的主要治疗方法是避免食物；然而，由于在许多食物中使用牛奶、鸡蛋、花生和坚果，它们的存在通常不会被预料到，意外和危险的暴露是常见的。最近，我们发现了一种新的肠腔可溶性抗原采样机制，这种机制是由杯状细胞(GC)抗原传代(GAP)10介导的。在初步研究中，我们发现了一条调节GAP形成的新途径，以及该途径在特应性易感小鼠对食物的临床反应性发展和急性食物过敏反应发生中的重要作用。我们的中心假设是，GAP介导的肠道抗原传递启动了“致敏食物过敏状态”，并刺激了临床对食物的反应。该提案中概述的具体目标将直接测试GAP形成在促进食品抗原呈递、致敏食品过敏状态的发展和对食品的临床反应性方面的参与。关于预期结果，建议的研究有望证明：目的i)GAP是SI食物抗原传递到免疫系统的主要途径；目的ii)胆碱能诱导的GAP通过加强食物抗原的传递而促进特应性易感人群的“致敏食物过敏状态”；以及目的III)MC衍生的IL-13在接近GCs的地方诱导GAP形成，从而增加抗原的输送和引发食物过敏反应的发生。拟议研究的成功完成将为我们目前对肠道管腔抗原采样的潜在机制和对食物的临床反应性的发展提供一个新的和实质性的背离，并确定差距作为开发治疗干预措施以防止新的食物过敏发展的有吸引力的目标。

 DESCRIPTION (provided by applicant): Food allergy is a serious and common disorder within the U.S. and is thought to impact 1 in 4 families. The main approved therapy for food allergy is food avoidance; however, with the use of milk, eggs, peanuts and tree nuts in many foods in which their presence might not normally be anticipated, accidental and dangerous exposures are common. Recently, we identified a new mechanism of intestinal luminal soluble antigen sampling, which was mediated by goblet cell (GC) antigen passages (GAPs) 10. In preliminary studies, we identified a new pathway in the regulation of GAP formation and an important role for this pathway in atopic susceptible mice in both the development of clinical reactivity to foods and onset of an acute food allergic reaction. Our central hypothesis is that GAP-mediated intestinal antigen delivery primes for the "sensitized food allergic state" and stimulates clinical reactivity to foods. The Specific Aims outlined in this proposal will directly est the involvement of GAP formation in the facilitation of food antigen presentation, development of the sensitized food allergic state and clinical reactivity to foods. With respect to the expected outcomes, the studies proposed are expected to demonstrate that: Aim I) GAPs are the primary pathway of SI food antigen delivery to the immune system; Aim II) that cholinergic-induced GAPs promote the "sensitized food allergic state" in atopic susceptible" individual by enhancing the delivery of food antigens; and Aim III) MC-derived IL- 13 in close proximity to GCs induces GAP formation, thereby augmenting antigen delivery and onset of a food- induced anaphylactic reaction. Successful completion of the proposed studies will provide a new and substantive departure from our current understanding of the underlying mechanisms of intestinal luminal antigen sampling and development of clinical reactivity to foods and identify GAPs as an attractive target for the development of therapeutic intervention to prevent development of new food allergies.