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（由应用程序提供）：该项目测试免疫球蛋白G（IgG）抗体在抑制食物过敏发展和在既定过敏的情况下恢复耐受性方面的功能。我们针对花生的IgG的初步数据阻止了对花生的敏感性，并且我们假设这可能是由于沉默的肥大细胞激活，即我们先前证明的免疫细胞的激活，以扩大过敏反应的发展。我们将研究IgG是否需要抑制性受体FcγR2B，以抑制过敏反应。我们还将研究IgG对树突状细胞的影响，后者是免疫反应的启动者，并携带抑制性FcγR2B并激活IgG的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接收器下游的键信号分子（SYK，SHP1）的重要性来证实。这些目标将使用新的鲁棒花生过敏模型进行测试，其中小鼠暴露了类似于人类患者的敏感性和过敏反应。特定的免疫细胞和分子的功能将使用一般工程的小鼠和药物方法进行测试。具体目的如下：目标1：确定FcγR2B是否取消了肥大细胞的正确效果。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Treg：Th2平衡。目标2：阐明对摄入的过敏原诱导IgG增强耐受性的机制。被检验的假设是IgG在肠道树突状细胞上连接FcγR2B，通过SHP-1作用以促进口服耐受性，同时限制了由FcγR3和SYK诱导的促促异化性细胞因子。目标3：测试花生特异性IgG的细胞和分子机制作为常规OIT的辅助。正在检验的假设是，通过FcγR2B作用的IgG将在抑制Th2响应的同时增强TREG响应。预计该项目将产生有关胃肠道中发生的食物过敏原的免疫敏感性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，这种疾病在发达国家迅速增加，没有批准的治疗方法。重要的是，该提案将扩大我们对IgG在食品过敏中的行为的了解，并可能为其用作治疗提供合理的基础。