Interleukin-9 In Experimental Intestinal Anaphylaxis

描述（由申请人提供）：食物过敏影响大约5%的美国人。食物过敏性反应是食物过敏最严重的形式，每年造成大约100人死亡。食物过敏领域的一个基本问题是了解易致食物过敏和过敏反应的分子机制。通过对IL-9缺乏小鼠、肠道IL-9转基因小鼠和食物过敏实验模型的初步分析，我们发现IL-9能显著增加肠道肥大细胞、肠道通透性和食物过敏易感性。本应用的目的是确定参与il -9介导的肠道过敏反应易感性的分子机制。本建议的工作假设是IL-9是一种刺激物，是诱导实验性肠过敏反应所必需的。中心假设将在三个目标中得到解决。在Aim 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在肠道过敏反应免疫病理中的作用。在Aim 2中，我们将描述胃肠道中IL-9过表达、肠道通透性和口腔抗原致敏易感性之间的关系。在Aim 3中，我们将定义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。我们希望发现IL-9在肠道炎症反应的不同组成部分和口服抗原诱导的肠道过敏反应的易感性的调节中起核心作用。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所涉及的分子过程将为具体预防和治疗这些疾病提供新的和创新的方法。叙述：食物过敏和过敏反应在西方世界越来越重要。我们的假设是细胞因子IL-9选择性地刺激肥大细胞依赖通路，促进口腔抗原致敏和食物过敏的发生。确定食物过敏易感性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.