Mast cell regulation of Th2 induction and tolerance breakdown in food allergy

虽然食物过敏已经成为一个主要的健康问题，但治疗选择相当有限。有一个 迫切需要确定引发和维持过敏的特定环境和内源性因素 对食物的反应，从而可以开发新的基于机制的疗法。我们发现了，伊格- 激活的肥大细胞，以引起包括食物过敏在内的即刻过敏反应而闻名， 实际上作为食物过敏原感受器和2型免疫反应佐剂发挥着单独但关键的作用 食物特异性IgE对肥大细胞的激活作用可以被猪瘟病毒的抗体所对抗。 相应的特异性。然而，重要的问题仍然没有得到回答：1)哪些具体方面 2型免疫(Th2，ILC2，IgE B细胞)被IgE激活的肥大细胞增强？，2)这些效应 肥大细胞因子介导的，3)免疫球蛋白抗体在体内的保护作用，抑制Th2和 通过FcgR2b介导的增强Treg反应，特别是在肥大细胞中 是否可以通过使用特定的单抗来激活它来减弱对食物过敏原的反应 抑制途径？本项目将在以下目标下回答这些问题： 目标1：确定IgE激活的肥大细胞如何促进食物过敏： 1.1检测体内IgE激活的肥大细胞对Th2、Tfh和IgE B细胞产生的影响 评价肥大细胞来源的Th2细胞因子的作用 1.2检测肥大细胞对新出现的效应器RORGT与致病的GATA-3、IRF-4、IL-4 Treg的作用 1.3评估TGFb介导的Treg对肥大细胞功能的相互抑制作用 1.4检测IgE激活的肥大细胞对体内ILC2诱导的影响：肥大细胞与肠道的作用 上皮细胞衍生的细胞因子 目的2：确定Ig G：FcgR2b信号如何在食物过敏中重置免疫反应： 2.1评价肥大细胞中的免疫球蛋白抑制信号在2型抑制和修复中的直接作用 食物过敏中功能性Treg反应的研究进展 2.2评价高亲和力人花生特异性抗体(及其免疫球蛋白)的免疫效果 亚类互换变异体)克隆的单个B细胞转录本对IgE介导的嗜碱性细胞活化的影响 2.3使用我们的花生过敏人源化小鼠模型来测试花生特异性单抗的效果 即刻过敏反应(全身性过敏反应)。 2.4检测免疫球蛋白对人源化小鼠Th、Tfh和Treg反应的影响

While food allergy has emerged as a major health issue, treatment options are quite limited. There is an urgent need to identify the specific environmental and endogenous factors that prime and then sustain allergic responses to foods so that new mechanism-based therapies can be developed. We have found that, IgE- activated mast cells, best known for causing immediate hypersensitivity reactions including food anaphylaxis, actually play a separate but critical role as food allergen sensors and adjuvants for Type 2 immune responses and that the activating effects of food-specific IgE on mast cells can be countered by IgG antibodies of corresponding specificity. Important questions remain unanswered, however: 1) What specific aspects of Type 2 immunity (Th2, ILC2, IgE+ B cells) are enhanced by IgE-activated mast cells?, 2) Are these effects mediated by mast cell cytokines?, 3) Is the protective effect of IgG antibodies in vivo, suppressing Th2 and enhancing Treg responses, mediated by their negative signals, delivered via FcgR2b, specifically in mast cells and can responses to food allergens be attenuated by using specific monoclonal IgG antibodies to activate this suppressive pathway? These questions will be answered in this project under the following aims: AIM 1: Establish how IgE-activated mast cells promote food allergy: 1.1 Test the impact of IgE-activated mast cells in vivo on emergence of Th2, Tfh and IgE+ B cells and evaluate the contributions of mast cell derived Th2 cytokines 1.2 Examine mast cell effects on emerging effector RORgt+ vs. pathogenic GATA-3+, IRF-4+, IL-4+ Treg 1.3 Evaluate reciprocal TGFb-mediated inhibitory effects of Treg on mast cell functions 1.4 Examine the influence of IgE-activated mast cells on ILC2 induction in vivo: Roles of mast cell- vs. gut epithelial cell-derived cytokines AIM 2: Determine how IgG:FcgR2b signals can reset the immune response in food allergy: 2.1 Evaluate the direct role of IgG inhibitory signals in mast cells in suppression of Type 2 and restoration of functional Treg responses in food allergy 2.2 Evaluate the effects of high-affinity human monoclonal peanut specific IgG antibodies (and their IgG subclass swap variants) cloned from single B cells transcriptomes on IgE-mediated basophil activation 2.3 Use our humanized mouse model of peanut allergy to test the effects of monoclonal peanut-specific IgE on immediate hypersensitivity responses (systemic anaphylaxis). 2.4 Test IgG effects on Th, Tfh and Treg responses in the humanized mice