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

描述（由申请人提供）：食物过敏研究联盟（CoFAR）已经开始了一系列旨在解决食物过敏的病因和潜在治疗方法的研究。其中一项计划中的临床试验将评估逐步口服花生过敏原（口服免疫疗法或OIT）对保护患者免受过敏反应并最终治愈过敏的有效性。花生过敏患者对花生过敏原有免疫反应，导致免疫球蛋白E （IgE）的产生。IgE与免疫细胞（如嗜碱性细胞）上的受体结合，当它与花生过敏原接触时，会导致组胺和其他物质的释放。已有研究表明，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抗体可能具有保护作用，尽管其保护机制尚不清楚。此外，通过一种鲜为人知的称为“临床脱敏”的过程，OIT似乎通过使人们对额外的意外暴露不那么敏感来保护人们免受严重反应。先前的研究表明，IgG通过与嗜碱性细胞上的抑制性IgG受体相互作用来抑制IgE，尽管其他研究表明，IgG可能只是阻止过敏原与IgE结合。迄今为止，还没有研究的设计方式允许在临床试验的背景下对这些替代机制进行个体评估。我们假设，OIT诱导抑制免疫变化，阻止ige诱导的嗜碱性粒细胞组胺的释放。我们想通过关注三个目标来验证我们的假设：首先，我们想确定OIT诱导抑制IgG的频率。其次，我们想要确定IgG是否主要阻断来自IgE的过敏原或与嗜碱性细胞上的抑制受体相互作用。第三，我们想了解过敏原的逐渐引入和快速（数小时到数天）升级到先前会引起反应（临床脱敏）的剂量如何影响患者的嗜碱性细胞。为了做到这一点，我们打算利用我们在流式细胞术中测量嗜碱性粒细胞激活的累积经验，并首次开始直接检测通过IgE和IgG受体刺激细胞产生的细胞内信号。我们相信我们有一个独特的机会来进行一个小型的，独立的研究项目，补充已经资助的口服免疫治疗食物过敏的大型前瞻性临床研究。该项目有潜力为口服免疫治疗的机制提供新的和独特的见解，并建立通过直接测量细胞内信号分子来评估嗜碱性粒细胞活化的创新方法。

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.