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，影响美国超过200万儿童。本提案的总体目标是检查通过I型IL-4受体的IL-4 Ra链调节信号传导的结构域对1）免疫致敏和2）诱导肠道过敏反应的作用。在过敏倾向个体中，食物摄入可导致Th 2极化的CD 4 + T辅助细胞的产生，其协调过敏性炎症的诱导和特异性IgE抗体的产生。在个体之间就产生Th 2应答的倾向而言存在显著的异质性，但在所有情况下，这都严重依赖于IL-4。我们假设，放大IL-4 Ra信号传导的结构变化将增强对过敏原的免疫致敏性。在食物过敏的情况下，具有相似IgE水平的不同受试者所表现出的过敏反应的严重程度存在关键的第二水平异质性。IL-4信号转导已被证明可以调节过敏反应的敏感性，我们假设它可以类似地调节食物过敏原刺激后的生理变化。其他特应性疾病与IL-4/13细胞因子/受体轴（包括IL-4 Ra 1）组分的多态性有关，最近的一些初步发现表明与食物过敏有潜在联系。我们假设IL-4受体-α链结构的改变增强了阳性信号或减弱了抑制信号，这将通过以下方式在食物过敏的鼠模型中引起夸大的食物过敏反应：1）增强致敏性和2）增强效应器反应。我们将通过执行以下操作来测试此假设：1。在具有影响信号传导的IL-4 Rachain变体的靶向插入的小鼠中对模型食物过敏原卵清蛋白（OVA）的免疫致敏的详细表征2.分析IL-4 Ra信号传导对食物过敏原应答的效应期的影响。食物过敏已成为发达国家的主要健康问题，估计儿童患病率高达6%，成人患病率高达3%。很难引起对摄入物质的免疫应答，使得在动物模型中进行食物过敏的研究成为一个挑战。在这项提案中，新的小鼠品系IL-4 Ra Y 709 F，对食物产生免疫反应非常敏感，将用于研究食物过敏的机制。

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.