Role of IL-4R-alpha signaling in food allergen sensitization and anaphylaxis

描述(由申请人提供)：食物过敏是一种日益普遍的疾病，影响着美国200多万儿童。这项提案的总体目标是研究通过I型IL-4受体的IL-4Ra链调节信号的结构域在1)免疫敏化和2)在肠道中诱导过敏反应方面的作用。在易过敏的人中，食物摄入可导致Th2极化的CD4+T辅助细胞的产生，该细胞协调过敏性炎症的诱导和特异性IgE抗体的产生。在产生Th2反应的倾向方面，个体之间存在显着的异质性，但在所有情况下，这都严重依赖于IL-4。我们假设，放大IL-4ra信号的结构变化将增强对过敏原的免疫敏感性。在食物过敏的情况下，对于具有相似IgE水平的不同受试者表现出的过敏反应的严重程度，存在关键的第二水平的异质性。IL-4信号已被证明可以调节对过敏反应的敏感性，我们假设它可能类似地调节食物过敏原攻击时的生理变化。其他特应性疾病与包括IL-4Ra1在内的IL-4/13细胞因子/受体轴成分的多态有关，最近的一些初步发现表明可能与食物过敏有关。我们假设，IL-4受体--一种增强积极信号或抑制信号的链结构的变化将通过以下方式在食物过敏的小鼠模型中引起夸大的食物过敏反应：1)增强敏化和2)增强效应反应。我们将通过执行以下操作来验证这一假设：1.通过定向插入影响信号的IL-4rachain变体的小鼠对模型食物过敏原卵清蛋白(OVA)的免疫增敏的详细特征2.分析IL-4ra信号对食物过敏原反应的效应阶段的影响。在发达国家，食物过敏已成为一个主要的健康问题，据估计，儿童的患病率高达6%，成年人的患病率高达3%。很难对摄入的物质产生免疫反应，这使得在动物模型中研究食物过敏成为一项挑战。在这项建议中，新的小鼠品系IL-4Ra Y709F将被用于研究食物过敏的机制。IL-4Ra Y709F对食物产生免疫反应非常敏感。

DESCRIPTION (provided by applicant): Food allergy is an increasingly prevalent condition, affecting more than 2 million children in the U.S. The overall goal of this proposal is to examine the roles of domains which regulate signaling by the IL-4Ra chain of the Type I IL-4 receptor on 1) immune sensitization and 2) induction of allergic responses in the intestine. In allergy-prone individuals, food ingestion can lead to the generation of Th2 polarized CD4+ T helper cells which orchestrate both the induction of allergic inflammation and the production of specific IgE antibodies. There is significant heterogeneity among individuals with respect to the tendency to generate Th2 responses but in all cases this is critically-dependent on IL-4. We hypothesize that variations in structure which amplify IL-4Ra signaling will enhance immune sensitization to allergens. In the case of food allergy, there is a critical second level of heterogeneity regarding the severity of allergic responses exhibited by different subjects with similar IgE levels. IL-4 signaling has been shown to modulate sensitivity to anaphylaxis and we hypothesize that it may similarly regulate physiologic changes upon food allergen challenge. Other atopic conditions have been linked to polymorphisms in components of the IL-4/13 cytokine/receptor axis including IL-4Ra1 and some recent preliminary findings suggest potential links to food allergy. We hypothesize that alterations in IL-4 receptor-a chain structure which enhance positive signals or dampen inhibitory signals will give rise to exaggerated food allergy responses in a murine model of food allergy by: 1) enhancing sensitization and 2) augmenting effector responses. We will test this hypothesis by performing: 1. Detailed characterization of immune sensitization to the model food allergen, ovalbumin (OVA), in mice with targeted insertion of IL-4Rachain variants affecting signaling 2. Analysis of IL-4Ra signaling effects on effector phase of response to food allergen. Food allergy has become a major health issues in developed countries with an estimated prevalence of up to 6% in children and 3% in the adult population. It is difficult to elicit immune responses to ingested substances making studies of food allergy in animal models a challenge. In this proposal novel strain of mice, IL-4Ra Y709F, highly susceptible to developing immune responses to foods, will be used to study mechanisms of food allergy.