Interleukin-9 In Experimental Intestinal Anaphylaxis

描述(由申请人提供)：在美国，大约5%的人对食物过敏。食物过敏是最严重的食物过敏形式，每年导致约100人死亡。食物过敏领域的一个基本问题是了解食物过敏和过敏反应的分子机制。在初步分析中，利用IL-9缺陷小鼠、肠道IL-9转基因小鼠和食物过敏(肠道过敏)的实验模型，我们证明了IL-9能显著增加肠道肥大细胞、肠道通透性和食物过敏的易感性。本应用的目的是确定IL-9介导的肠道过敏易感性的分子机制。这一建议的工作假设是，IL-9是一种刺激物，是诱导实验性肠道过敏反应所必需的。核心假设将通过三个目标加以阐述。在目标1中，我们将使用IL-9缺陷、IL-9R缺陷和WT小鼠以及我们的肠道过敏反应实验模型来确定IL-9在肠道过敏反应的免疫病理学中的作用。在目标2中，我们将阐明IL-9在胃肠道的过度表达、肠道通透性与口服抗原致敏易感性的关系。在目标3中，我们将确定肥大细胞和血小板激活因子在IL-9诱导的肠道通透性改变中的作用。我们期望发现IL-9在调节肠道炎症反应的不同成分以及对口服抗原诱导的肠道过敏反应的易感性中起着中心作用。这些结果将对人类健康产生重要的积极影响，因为识别与食物过敏原致敏和过敏反应有关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的途径，促进口服抗原敏化和食物过敏的发生。明确食物过敏易感性的生物学过程将促进我们对这些复杂而鲜为人知的临床事件的了解，并适用于其他过敏性疾病的预防/治疗，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.