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

描述(由申请人提供)：食物过敏是一种常见的疾病，与严重的发病率和死亡率有关。目前还没有有效的预防措施或治疗方法，诊断工具也不完善。这种情况需要创新的策略来精确定义食物过敏中的分子和细胞途径，以便能够识别预测过敏反应风险的新的诊断标记，从而能够识别新的候选治疗靶点。已知的几种特应性疾病与IL-4/13受体组分的激活多态性之间的关联，以及我们对携带IL-4R激活变体的小鼠强烈食物过敏反应的初步观察，支持了我们的中心假设：IL-4信号在食物过敏中起关键作用，驱动TH2反应，肥大细胞扩张和抑制Treg。在细胞内IL-4R的抑制性ITIM基序被破坏的F709小鼠将被用来检验这一假设。不像 它们的野生型Y709对食物抗原具有耐受性，它们对摄取的蛋白质、肠道肥大细胞扩张和肠道攻击时的全面过敏反应产生强大的IgE反应。这种表型在小鼠食物过敏模型中是独一无二的，与人类的食物过敏非常相似。F709系统为集中分析IL-4对肥大细胞、T细胞和肠上皮的直接影响以及对 探讨肥大细胞、IgE抗体、TH2和Treg细胞在食物过敏发生发展中的相互作用。我们的假设将以以下目的进行验证：目的1：确定增强的IL-4信号对食物过敏中肥大细胞反应性、蛋白酶表型、基因表达和稳态的影响，以及IL-4R对靶组织对介质敏感性和肠道通透性的影响。目的2：检测肥大细胞和IgE抗体对F709小鼠免疫增敏(体液和TH2反应)和调节性T细胞(Treg)诱导的影响。目的3：通过确定肥大细胞、T细胞、在IL-4信号增强的情况下，靶组织和肠道上皮在食物过敏原反应中的作用，这些研究将确定除了特定的IgE产生外，将个人置于食物过敏反应风险中的关键因素。这有可能导致 应用于食物过敏的新诊断标记物和确定已建立的食物过敏治疗的候选靶点。

DESCRIPTION (provided by applicant): Food allergy is a prevalent disorder associated with significant morbidity and mortality. There are currently no effective preventive measures or cures and tools for diagnosis are imperfect. This situation calls for innovative strategies to precisely define the molecular and cellular pathways in food allergy both so that novel diagnostic markers predicting risk of allergic reaction can be identified and so that new candidate targets for therapy can be identified. The known associations of several atopic conditions with activating polymorphisms in components of IL-4/13 receptors, along with our preliminary observation of intense food anaphylaxis in mice harboring an activating variant of IL-4R¿, provide support for our central hypothesis: that IL-4 signaling is critical in food anaphylaxi, driving TH2 responses, mast cell expansion and suppression of Treg. F709 mice, in which the inhibitory cytosolic ITIM motif of IL-4R¿ is disrupted, will be used to test the hypothesis. Unlike their wild-type Y709 counterparts which are tolerant to dietary antigens, they develop robust IgE responses to ingested proteins, intestinal mast cell expansion and full-blown anaphylactic reactions upon enteral challenge. This phenotype is unique among murine food allergy models, closely mimicking food allergy in humans. The F709 system provides a powerful resource both for focused analysis of direct IL-4 effects on mast cells T cells and intestinal epithelium and for probing the interactions between mast cells, IgE antibodies, TH2 and Treg cells in the development of food allergy. Our hypothesis will be tested with the following aims: AIM 1: To define effects of enhanced IL-4 signaling on mast cell responsiveness, protease phenotype, gene expression and homeostasis in food allergy and to test IL-4R effects on target tissue sensitivity to mediators and on intestinal permeability AIM 2: To test mast cell and IgE antibody effects on immune sensitization (humoral and TH2responses) and on regulatory T cell (Treg) induction in F709 mice AIM 3: To examine the effects of pharmacologic mast cell inhibition or IgE blockade on immune sensitization to food allergens and on regulation of established responses Anticipated outcome: By defining specific alterations in mechanisms of mast cell, T cell, target tissue and gut epithelial functions in food allergen responses occurring in the settin of enhanced IL-4 signals, these studies will establish the critical factors, in addition to specifi IgE production, that place individuals at risk for food anaphylaxis. This has the potential to lead to both novel diagnostic markers for food allergy and to the identification of candidate targets fo therapy in established food allergy.