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

描述（由申请方提供）：本项目检测免疫球蛋白G（IgG）抗体在抑制食物过敏发展和恢复已确定过敏背景下耐受性方面的功能。我们的初步数据表明，抗花生的IgG可以防止对花生的致敏，我们假设这可能是由于沉默了肥大细胞的激活，我们以前已经证明了免疫细胞可以放大过敏反应的发展。我们将研究IgG是否需要抑制性受体Fcγ R2 b来抑制过敏反应。我们还将研究IgG对树突状细胞的影响，树突状细胞是免疫应答的启动者，携带IgG的抑制性Fcγ R2 b和激活性FcγR3受体。这些受体的正信号和负信号的贡献将通过检查细胞内受体下游的关键信号分子（Syk，Shp 1）的重要性来证实。这些目标将使用一种新的强大的花生过敏小鼠模型进行测试，其中小鼠表现出与人类患者相似的致敏和过敏反应。将使用基因工程小鼠和药物方法测试特定免疫细胞和分子的功能。具体目的如下：目的1：确定Fcγ R2 b是否能取消肥大细胞的佐剂效应。正在检验的假设是IgG与肥大细胞上的Fcγ R2 b结合，产生抑制信号以恢复Treg：Th 2平衡。目的2：阐明IgG增强机体对摄入性过敏原耐受的机制。正在检验的假设是IgG连接肠道树突状细胞上的Fcγ R2 b，通过Shp-1发挥作用以促进口服耐受，同时限制FcγR3和Syk诱导的促过敏细胞因子。目的3：探讨花生特异性IgG作为常规OIT辅助治疗的细胞和分子机制。正在测试的假设是IgG通过Fcγ R2 b起作用，将增强Treg应答，同时抑制Th 2应答。该项目预计将产生关键的新信息的基本机制的免疫致敏发生在胃肠道的食物过敏原。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，这种疾病在发达国家迅速增加，并且没有批准的治疗方法。重要的是，这一建议将扩大我们对IgG在食物过敏中的作用的认识，并可能为其作为一种治疗方法提供合理的依据。

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.