Food Allergy and Goblet Cell Antigen Passages

 描述（由申请人提供）：食物过敏是美国一种严重和常见的疾病，被认为影响四分之一的家庭。食物过敏的主要批准疗法是避免食物;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期，意外和危险的暴露是常见的。最近，我们确定了一种新的机制，肠腔可溶性抗原采样，这是介导的杯状细胞（GC）抗原通道（GAP）10。在初步研究中，我们确定了一个新的途径，在调节GAP的形成和一个重要的作用，这一途径在特应性易感小鼠的发展中的临床反应的食物和急性食物过敏反应的发病。我们的中心假设是GAP介导的肠道抗原传递引发了“致敏食物过敏状态”，并刺激了对食物的临床反应。本提案中概述的具体目标将直接评估GAP形成在促进食物抗原呈递、致敏食物过敏状态的发展和对食物的临床反应性中的参与。关于预期的结果，所提出的研究预期将证明：目的I）GAP是SI食物抗原递送至免疫系统的主要途径;目的II）胆碱能诱导的GAP通过增强食物抗原的递送而促进特应性易感个体中的“致敏食物过敏状态”;和目的III）MC-衍生的IL- 13在GC附近诱导GAP形成，从而增强抗原递送和食物诱导的过敏反应的发生。成功完成拟议的研究将提供一个新的和实质性的偏离，从我们目前的理解的基本机制的肠腔抗原采样和发展的临床反应性的食物，并确定GAP作为一个有吸引力的目标，为发展的治疗干预，以防止发展新的食物过敏。

 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.