Mechanisms of oral immunotherapy-induced suppression of type I hypersensitivity.

口服免疫疗法诱导抑制 I 型超敏反应的机制。

• 批准号: 8013729
• 负责人: WAYNE G SHREFFLER
• 金额: $ 4.74万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013729
• 关键词: Accounting; Address; Adult; Affect; Allergen Immunotherapy; Allergens; Allergic; Allergic Reaction; Allergy to peanuts; Anaphylaxis; Antibodies; Basophils; Binding; Cell physiology; Cells; Cessation of life; Child; Clinical; Clinical Research; Clinical Trials; Complement; Complex; Dose; Down-Regulation; Effectiveness; Effector Cell; Epitopes; Etiology; Evaluation; Event; Flow Cytometry; Food; Food Hypersensitivity; Funding; Histamine Release; Hour; Hypersensitivity; IgE; IgG Receptors; Immediate hypersensitivity; Immune; Immune response; Immunoglobulin G; Immunotherapy; In Vitro; Individual; Lead; Measurement; Measures; Mediating; Methods; Mus; Oral; Oral cavity; PTPN11 gene; Patients; Peanuts - dietary; Phase; Phenotype; Phosphorylation; Play; Process; Production; Reaction; Receptor Signaling; Refractory; Research; Research Project Grants; Role; SYK gene; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Staining method; Stains; Testing; Time; base; clinical efficacy; desensitization; design; experience; in vivo; innovation; insight; mast cell; novel; peripheral blood; prevent; prospective; public health relevance; receptor; receptor binding; sublingual immunotherapy

DESCRIPTION (provided by applicant):The Consortium of Food Allergy Research (CoFAR) has begun a series of studies intended to address both the etiology of and potential cure for food allergy. One of the planned clinical trials will evaluate the effectiveness of gradually administering peanut allergen by mouth (oral immunotherapy or OIT) on protecting patients from allergic reactions and ultimately curing them of their allergy. Patients with peanut allergy have an immune response to peanut allergens that results in the production of immunoglobulin E (IgE). IgE is bound by receptors on immune cells, such as basophils, and can lead to the release of histamine and other substances when it comes into contact with peanut allergen. It has been shown that OIT can induce the production of allergen-specific immunoglobulin G (IgG) antibody. This IgG antibody, in contrast to IgE antibody, may be protective, though the mechanism of its protection is not well understood. In addition, by a poorly understood process termed, `clinical desensitization', OIT appears to protect people from severe reactions by making them less sensitive to additional accidental exposures. Previous studies have suggested that IgG inhibits IgE by interacting with inhibitory IgG receptors on basophils, although other studies have suggested instead that IgG may simply prevent allergen from binding to the IgE. To date, no studies have been designed in such a way as to allow evaluation of these alternative mechanisms on an individual basis in the context of a clinical trial. We hypothesize, that OIT induces inhibitory immune changes that prevent the IgE-induced release of histamine from basophils. We would like to test our hypothesis by focusing on three aims: First, we would like to establish how frequently inhibitory IgG is induced by OIT. Second, we would like to determine whether IgG is primarily blocking allergen from IgE or interacting with inhibitory receptors on basophils. Third, we would like to understand how gradual introduction and rapid (hours to days) escalation of allergen to a dose that would previously have caused a reaction (clinical desensitization) affects patients' basophils. In order to do this, we intend to take advantage of our cumulative experience in measuring basophil activation by flow cytometry, and begin for the first time to directly examine intracellular signals that result from the stimulation of the cells via the IgE and IgG receptors. We believe we have a unique opportunity to conduct a small, self-contained research project that complements an already funded large prospective clinical study of oral immunotherapy for food allergy. This project has the potential both to give new and unique insight into the mechanisms of oral immunotherapy and to establish innovative methods for the assessment of basophil activation by direct measurement of intracellular signaling molecules. PUBLIC HEALTH RELEVANCE Food allergy affects 6-8% of children and 2-4% of adults and is increasing. Food allergy accounts for approximately 30,000 episodes of anaphylaxis and 100-200 deaths. This proposal is to study how allergen immunotherapy can protect people so that ultimately it can be more effective.

描述（由申请人提供）：食品过敏研究联盟（Cofar）已开始进行一系列研究，旨在解决食品过敏的病因和潜在治疗。一项计划的临床试验将评估通过口腔（口服免疫疗法或OIT）逐渐给予患者免受过敏反应并最终治愈其过敏的有效性。花生过敏的患者对花生过敏原有免疫反应，从而导致免疫球蛋白E（IgE）产生。 IgE受到免疫细胞（例如嗜碱性粒细胞）的受体结合，并且在与花生过敏原接触时可能导致组胺和其他物质释放。已经表明，OIT可以诱导过敏原特异性免疫球蛋白G（IgG）抗体的产生。与IgE抗体相比，这种IgG抗体可能具有保护性，尽管其保护的机制尚不清楚。此外，通过所谓的“临床脱敏”过程，OIT似乎可以通过使人们对额外的意外暴露敏感，从而保护人们免受严重反应的影响。先前的研究表明，IgG通过与嗜碱性粒细胞上的抑制性IgG受体相互作用来抑制IgE，尽管其他研究表明IgG可以简单地阻止过敏原与IgE结合。迄今为止，尚未以这种方式设计研究，以便在临床试验的背景下以个人为基础评估这些替代机制。我们假设OIT会诱导抑制性免疫变化，以防止IgE诱导的组胺从嗜碱性粒细胞释放。我们想通过关注三个目标来检验假设：首先，我们想确定OIT诱导抑制性IgG的频率。其次，我们想确定IgG是主要阻止过敏原与嗜碱性粒细胞上的抑制受体相互作用。第三，我们想了解过敏原逐渐引入和快速（数小时至几天）升级为以前会导致反应（临床脱敏）的剂量会影响患者的嗜碱性粒细胞。为了做到这一点，我们打算利用我们通过流式细胞术测量嗜碱性粒细胞激活的累积经验，并首次开始直接检查通过IgE和IgG受体刺激细胞引起的细胞内信号。我们认为，我们有一个独特的机会来开展一个小型的独立研究项目，该项目补充了一项针对食物过敏的口服免疫疗法的大型前瞻性临床研究。该项目具有对口服免疫疗法机制的新和独特的见解，并通过直接测量细胞内信号分子来评估嗜碱性粒细胞激活的创新方法。 公共卫生相关性食品过敏会影响6-8％的儿童和2-4％的成年人，并且正在增加。食物过敏约为过敏反应和100-200例死亡。该建议是研究过敏原免疫疗法如何保护人，以最终可以更有效。