IgG and Fc gamma receptor regulation of food allergy and oral tolerance

描述(由申请人提供)：该项目测试免疫球蛋白G(IgG)抗体在抑制食物过敏发展和恢复对已建立的过敏的耐受性方面的功能。我们的初步数据表明，针对花生的免疫球蛋白可以防止花生致敏，我们假设这可能是由于沉默了肥大细胞的激活，我们之前已经证明，免疫细胞可以放大过敏反应的发展。我们将研究免疫球蛋白是否需要抑制性受体Fcγr2b来抑制过敏反应。我们还将研究免疫球蛋白对树突状细胞的影响，树突状细胞是免疫反应的起始者，携带抑制性Fcγr2b和激活FcγR3受体。通过检测细胞内受体下游的关键信号分子(Syk，SHP1)的重要性，将证实来自这些受体的积极和消极信号的贡献。这些目标将使用一种新的健壮的花生过敏小鼠模型进行测试，在该模型中，小鼠表现出类似于人类患者的过敏和过敏反应。特定免疫细胞和分子的功能将使用基因工程小鼠和药物方法进行测试。具体目的如下：目的1：确定Fcγr2b是否取消肥大细胞的佐剂作用。正在测试的假设是，免疫球蛋白与肥大细胞上的Fcγr2b结合，产生抑制信号来恢复Treg：Th2平衡。目的：探讨免疫球蛋白增强小鼠对食入性变应原耐受性的机制。正在测试的假设是，免疫球蛋白将Fcγr2b连接到肠道树突状细胞上，通过SHP-1促进口服耐受，同时限制FcγR3和Syk诱导的促过敏细胞因子。目的3：检测花生特异性免疫球蛋白作为常规OIT的辅助物的细胞和分子机制。正在测试的假设是，通过Fcγr2b作用的免疫球蛋白将增强Treg反应，同时抑制Th2反应。该项目预计将产生关于对发生在胃肠道中的食物过敏原的免疫增敏的基本机制的关键新信息。这些数据将为开发新的、基于机制的食物过敏疗法奠定基础。食物过敏是一种在发达国家迅速增加的疾病，目前还没有得到批准的治疗方法。重要的是，这项建议将扩大我们对免疫球蛋白在食物过敏中作用的认识，并可能为其作为一种治疗方法提供合理的基础。

DESCRIPTION (provided by applicant): This project tests the functions of immunoglobulin G (IgG) antibodies in suppressing the development of food allergy and in restoring tolerance in the setting of established allergy. Our preliminary data that IgG against peanut prevents sensitization to peanut, and we hypothesize that this may be due to silencing the activation of mast cells, immune cells which we have previously shown to amplify the development of the allergic response. We will investigate whether IgG requires the inhibitory receptor, FcγR2b, in order to suppress the allergic response. We will also investigate the effects of IgG on dendritic cells, which are the initiators of immune responses and carry both inhibitory FcγR2b and activating FcγR3 receptors for IgG. The contributions of the positive and negative signals from these receptors will be corroborated by examining the importance of key signaling molecules (Syk, Shp1) downstream of the receptors inside the cells. These objectives will be tested using a new robust mouse model of peanut allergy in which the mice exhibit sensitization and anaphylaxis similar to that seen in human patients. The functions of specific immune cells and molecules will be tested using genetically engineered mice and pharmaceutical approaches. The specific aims are as follows: AIM 1: To determine whether FcγR2b cancels the adjuvant effect of mast cells. The hypothesis being tested is that IgG, binding to FcγR2b on mast cells, produces inhibitory signals to restore the Treg:Th2 balance. AIM 2: To elucidate the mechanisms of IgG-enhanced tolerance induction to ingested allergens. The hypothesis being tested is that IgG ligates FcγR2b on intestinal dendritic cells, acting via Shp-1 to promote oral tolerance, while limiting pro-allergenic cytokines induced by FcγR3 and Syk. AIM 3: To test the cellular and molecular mechanisms of peanut-specific IgG as an adjunct to conventional OIT. The hypothesis being tested is that IgG, acting via FcγR2b, will enhance Treg responses while suppressing Th2 responses. This project is expected to generate critical new information regarding the basic mechanisms of immune sensitization to food allergens occurring in the gastrointestinal tract. These data will lay the groundwork for the development of new, mechanism-based therapies for food allergy, a disorder that is rapidly increasing in developed nations and has no approved treatments. Importantly, this proposal will expand our knowledge of the actions of IgG in food allergy, and may provide a rational basis for its use as a therapy.