Interleukin-9 In Experimental Intestinal Anaphylaxis

描述（由申请人提供）：食物过敏影响美国约5%的个体。食物过敏是最严重的食物过敏形式，每年约有100人死于食物过敏。食物过敏领域的一个基本问题是了解易患食物过敏和过敏反应的分子机制。在初步分析中，采用IL-9缺陷小鼠、肠IL-9转基因小鼠和食物过敏（肠过敏反应）的实验模型，我们已经证明IL-9显著增加肠肥大细胞、肠通透性并易患食物过敏。本申请的目的是确定IL-9介导的肠道过敏反应易感性的分子机制。该建议的工作假设是IL-9是一种刺激物，并且是诱导实验性肠道过敏反应所必需的。中心假设将在三个目标。在目的1中，我们将采用IL-9缺陷型、IL-9 R缺陷型和WT小鼠以及我们的肠道过敏反应实验模型来确定IL-9在肠道过敏反应免疫病理学中的作用。在目的2中，我们将描述胃肠道中IL-9过表达、肠道通透性和口服抗原致敏倾向之间的关系。在目的3中，我们将确定肥大细胞和血小板活化因子在IL-9诱导的肠通透性改变中的作用。我们期望发现IL-9是调节肠道炎症反应的不同组分和口服抗原诱导的肠道过敏反应的易感性的核心。这些结果将对人类健康产生重要的积极影响，因为确定食物过敏原致敏和过敏反应的分子过程将为这些疾病的具体预防和治疗提供新的创新方法。我们的假设是细胞因子IL-9选择性地刺激肥大细胞依赖性途径，促进口服抗原致敏和食物过敏的发生。定义食物过敏易感性中涉及的生物学过程将促进我们对这些复杂且知之甚少的临床事件的理解，并适用于预防/治疗其他过敏性疾病，如湿疹和哮喘。

DESCRIPTION (provided by applicant): Food allergy affects approximately 5% of individuals in the USA. The most severe form of food allergy, food-induced anaphylaxis causes approximately 100 deaths per year. An essential question in the food allergy field is to understand the molecular mechanisms that predispose to food allergy and anaphylaxis. In preliminary analysis, employing IL-9 deficient mice, intestinal IL-9 transgenic mice and experimental models of food allergy (intestinal anaphylaxis) we have demonstrated that IL-9 profoundly increases intestinal mast cells, intestinal permeability and predisposes to food allergy. The objective of this application is to define the molecular mechanisms involved in IL-9-mediated predisposition to intestinal anaphylaxis. The working hypothesis of this proposal is that IL-9 is a stimulus and required for the induction of experimental intestinal anaphylaxis. The central hypothesis will be addressed in three aims. In Aim 1, we will employ IL-9-deficient, IL-9R-deficient and WT mice and our experimental model of intestinal anaphylaxis to define the role of IL-9 in the immunopathology of intestinal anaphylaxis. In Aim 2, we will delineate the relationship between IL-9 overexpression in the gastrointestinal tract, intestinal permeability and predisposition to oral antigen sensitization. In Aim 3, we will define the role of mast cells and platelet activating factor in IL-9-induced altered intestinal permeability. We expect to find that IL-9 is central to the regulation of different components of the intestinal inflammatory response and the predisposition to oral antigen-induced intestinal anaphylaxis. Such results will have an important positive impact on human health, as identification of the molecular processes involved in food allergen sensitization and anaphylaxis will provide new and innovative approaches for the specific prevention and treatment of these diseases.Narrative: Food allergy and anaphylaxis are of increasing importance in the western world. Our hypothesis is that the cytokine IL-9 selectively stimulates mast cell- dependent pathways and promotes oral antigen sensitization and the onset of food allergy. Defining the biological processes involved in food allergy susceptibility will advance our understanding of these complex and poorly understood clinical events, and be applicable to the prevention/treatment of other allergic disorders such as eczema and asthma.