Understanding the Mechanism of Mucosal Immunotherapy

描述（由申请人提供）：食物过敏是一种口腔耐受异常，在美国发生在6%的儿童和3.5%的成人中。花生过敏是最常见的食物过敏之一；大多数儿童在生命早期就会出现这种过敏，不能摆脱它，并且有严重和致命的过敏反应的风险。目前还没有针对花生过敏的积极治疗方法，但我们和其他人正在开发特定类型的免疫疗法，使这些患者不再对花生过敏。这项建议的重要性是基于我们具有里程碑意义的研究，这些研究检查了花生口服免疫疗法（OIT）的效果，显示花生过敏患者在治疗期间（脱敏）摄入的花生量大幅增加，并且在某些情况下，在停止治疗后会导致长期临床耐受性。我们已经确定了这些受试者中嗜碱性细胞/肥大细胞反应性、抗原特异性T细胞反应和全身体液免疫反应的初始变化。我们的假设是花生OIT会改变嗜碱性细胞/肥大细胞的早期信号通路，导致临床脱敏，然后由于过敏原特异性T细胞和b细胞的相关变化而产生临床耐受性。这项建议的长期目标是更好地了解接受过敏原免疫治疗的幼儿对食物产生口服耐受的机制。为了实现这一目标，我们的具体目标如下：目标1：确定花生OIT诱导花生过敏受试者嗜碱性细胞/肥大细胞对花生OIT的低反应性的机制；目标2：确定花生过敏原特异性CD4+ T细胞的频率和表型，以及Treg细胞的抑制功能，这些与花生临床耐受性的发展有关；目标3：确定花生特异性粘膜和全身体液免疫反应对OIT临床耐受性的影响。这些研究将帮助我们确定脱敏状态的机制和持久性，然后发展对油后食物的耐受性。花生过敏的治疗是迫切需要的，这些研究的完成将为OIT和其他类型的治疗的发展提供强有力的科学基础，希望产生对花生和其他食物的长期临床耐受性。

DESCRIPTION (provided by applicant): Food allergy, an aberration of oral tolerance, occurs in 6% of children and 3.5% of adults in the United States. Peanut allergy is one of the most common food allergies; most children develop this allergy early in life, do not outgrow it and are at risk for severe and life-ending anaphylactic reactions. Currently there is not a proactive treatment for peanut allergy but we along with others are developing specific types of immunotherapy that will cause these patients to be no longer allergic to peanuts. The significance of this proposal is based on our landmark studies that have examined the effects of peanut oral immunotherapy (OIT) showing a substantial increase in the amount of peanut that a peanut allergic patient can ingest while on therapy (desensitization) and in some cases causing long-term clinical tolerance when the therapy is discontinued. We have identified initial changes in basophil/mast cell reactivity, antigen-specific T cell responses and systemic humoral immune responses in these subjects. Our hypothesis is that peanut OIT will alter the early signaling pathways of basophils/mast cells causing clinical desensitization and then clinical tolerance will develop because of the interrelated changes in allergen-specific T- and B-cells. The long-term goal of this proposal is to better understand the mechanism of the development of oral tolerance to foods in young children treated with allergen immunotherapy. To accomplish this goal our specific aims are the following: Aim 1: Determine the mechanism(s) by which OIT induces hyporesponsiveness in basophils/mast cells in peanut allergic subjects on peanut OIT, Aim 2: Determine the peanut allergen-specific CD4+ T cell frequencies and phenotypes, as well as the suppressive function of Treg cells, that are associated with the development of clinical tolerance to peanuts, Aim 3: Determine the effect of peanut-specific mucosal and systemic humoral immune responses in OIT on clinical tolerance. The studies will help us identify the mechanism and durability of the desensitized state and then the development of tolerance to foods after OIT. A treatment for peanut allergy is critically needed, the completion of these studies will provide a strong scientific basis for the development of OIT and other types of therapy that hope to produce long-term clinical tolerance to peanuts and other foods. PUBLIC HEALTH RELEVANCE: Food allergy, an aberration of oral tolerance, occurs in 6% of children and 3.5% of adults in the United States. Peanut allergy is one of the most common food allergies; most children develop this allergy early in life, do not outgrow it and are at risk for severe and life-ending anaphylactic reactions. Currently there is not a proactive treatment for peanut allergy but we along with others are developing specific types of immunotherapy that will cause these patients to be no longer allergic to peanuts. The significance of this proposal is based on our landmark studies that have examined the effects of peanut OIT showing a substantial increase in the amount of peanut that a peanut allergic patient can ingest while on therapy (desensitization) and in some cases causing long-term clinical tolerance when the therapy is discontinued. The long- term goal of this proposal is to better understand the mechanism of the development of oral tolerance to foods in young children treated with allergen immunotherapy. .