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

IL-4R-α信号在食物过敏原致敏和过敏反应中的作用

基本信息

批准号：
7869772
负责人：
Hans C Oettgen
金额：
$ 21.43万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7869772
关键词：
Adult Affect Agonist Allergens Allergic inflammation Anaphylaxis Animal Model Antibodies Antibody Formation Antigens Asthma Atopic Dermatitis Attenuated B-Lymphocytes CD4 Positive T Lymphocytes Cell Count Cell Culture Techniques Cells Child Clinical Commit Cytokine Receptors Developed Countries Effector Cell Enteral Exhibits Food Food Hypersensitivity Funding Generations Genetic Polymorphism Goals Health Helper-Inducer T-Lymphocyte Heterogeneity Homeostasis Hypersensitivity IL-4R alpha ITIM IgE Immune Immune response Immunobiology Immunoglobulin Class Switching Individual Ingestion Interleukin 4 Receptor Interleukin-4 Intestinal Mucosa Intestines Knock-in Mouse Lead Link Modeling Mouse Strains Mus Ovalbumin Phase Phenotype Physiological Population Prevalence Production Reaction Recording of previous events Regulatory T-Lymphocyte Role Severities Signal Transduction Source Stimulus Structure Symptoms System Testing United States National Institutes of Health Variant allergic response atopy experience food allergen gastrointestinal in vivo mast cell mutant novel progenitor response

项目摘要

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.

描述（由申请人提供）：食物过敏是一种越来越普遍的状况，影响了美国的200万以上儿童，该提案的总体目标是检查域的作用1）免疫敏化和2）肠中的过敏反应。在容易过敏的个体中，食物摄入会导致Th2极化CD4+ T辅助细胞的产生，该细胞既策划过敏性炎症的诱导又产生特定的IgE抗体。个体之间在产生Th2响应的趋势方面存在明显的异质性，但是在所有情况下，这都至关重要。我们假设扩增IL-4RA信号传导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，关于不同受试者具有相似IgE水平的过敏反应的严重性，第二级的异质性是至关重要的。 IL-4信号传导已被证明可以调节对过敏反应的敏感性，我们假设它可能会在食物过敏原挑战时类似地调节生理变化。其他特应性条件与包括IL-4RA1在内的IL-4/13细胞因子/受体轴成分的多态性有关，以及最近的一些初步发现表明与食物过敏的潜在联系。我们假设IL-4受体A链结构的改变，从而增强正信号或抑制性信号会导致食物过敏模型的夸张食物过敏反应，从：1）增强敏化和2）增强效应子的反应。我们将通过执行：1。对模型食物过敏原（OVA）（OVA）的详细表征在具有目标插入IL-4RACHAN变体的小鼠中详细表征，影响信号2。对食物过敏原的反应。食物过敏已成为发达国家的主要健康问题，儿童的患病率估计高达6％，而成人人群的患病率为3％。很难引起对摄入的物质的免疫反应，使动物模型中的食物过敏研究成为挑战。在这一建议中，小鼠的新型菌株IL-4RA Y709F极易受到对食物的免疫反应的影响，将用于研究食物过敏的机制。