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

IgG 和 Fc γ 受体对食物过敏和口服耐受的调节

• 批准号: 8949448
• 负责人: Oliver Teal Burton
• 金额: $ 11.29万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8949448
• 关键词: Address; Adjuvant; Allergens; Allergic; Allergy to peanuts; Anaphylaxis; Antibodies; Basophils; Binding; Cells; Complement; Counseling; Data; Dendritic Cells; Developed Countries; Development; Disease; Enteral; Equilibrium; Etiology; Exhibits; Exposure to; Fc Receptor; Food; Food Hypersensitivity; Gastrointestinal tract structure; Gene Deletion; Genetically Engineered Mouse; Health; Healthcare; Human; Human Milk; Hypersensitivity; IgE; IgG Receptors; Immune; Immune response; Immune system; Immunoglobulin G; In Vitro; Individual; Industry; Infant; Ingestion; Interleukin-4; Intestines; Knowledge; Ligation; Mediating; Mentors; Milk; Modeling; Molecular; Molecular Target; Mothers; Mus; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Prevalence; Production; Receptor Signaling; Recommendation; Regulation; Regulatory T-Lymphocyte; Role; Signal Transduction; Signaling Molecule; Societies; T cell response; TNFRSF5 gene; Testing; Time; Transforming Growth Factor beta; Work; allergic response; base; crosslink; cytokine; feeding; food allergen; in vivo; insight; mast cell; mouse model; novel; novel strategies; oral immunotherapy; oral tolerance; prevent; receptor; reconstitution; response; targeted treatment; trafficking

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.

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的发展和在已确定过敏的情况下恢复耐受性的功能，我们的初步数据表明抗花生的 IgG 可以防止对花生过敏。我们认为这可能是由于肥大细胞的激活被抑制所致，我们之前已经证明肥大细胞可以放大过敏反应的发展，我们将研究 IgG 是否需要抑制作用。我们还将研究 IgG 对树突状细胞的影响，树突状细胞是免疫反应的发起者，并携带抑制性 FcγR2b 和激活性 FcγR3 受体对 IgG 的贡献。来自这些受体的信号将通过检查细胞内受体下游的关键信号分子（Syk、Shp1）的重要性得到证实。这些目标将通过使用进行测试。一种新的稳健的花生过敏小鼠模型，其中小鼠表现出与人类患者相似的过敏和过敏反应。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，具体目标如下：目标 1：确定 FcγR2b 是否取消肥大细胞的佐剂作用 所测试的假设是 IgG 与肥大细胞上的 FcγR2b 结合，产生抑制信号以恢复肥大细胞的佐剂作用。 Treg：Th2 平衡 目标 2：阐明 IgG 增强对摄入过敏原的耐受性诱导的机制 所测试的假设是 IgG 连接肠道树突状细胞上的 FcγR2b，通过 Shp-1 发挥作用，促进口服耐受性，同时限制亲-耐受性。 FcγR3 和 Syk 3 诱导的过敏性细胞因子：测试花生特异性 IgG 作为常规辅助剂的细胞和分子机制。 OIT。正在测试的假设是，IgG 通过 FcγR2b 发挥作用，将增强 Treg 反应，同时抑制 Th2 反应。这些数据预计将产生有关胃肠道中食物过敏原免疫致敏的基本机制的重要新信息。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且尚未获得批准的治疗方法的疾病，重要的是，该提案将扩大我们对食物过敏的了解。 IgG 在食物过敏中的作用，并可能为其用作治疗提供合理依据。