Understanding the Mechanism of Mucosal Immunotherapy

了解粘膜免疫治疗的机制

• 批准号: 7482336
• 负责人: A. Wesley Burks
• 金额: $ 38.26万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7482336
• 关键词: Adult; Age; Allergens; Allergic; Allergic Reaction; Allergy to eggs; Allergy to peanuts; American; Antigens; Appearance; Applications Grants; Basophils; Biological Assay; Blinded; Blocking Antibodies; CD4 Positive T Lymphocytes; Cell membrane; Cells; Child; Clinical; Clinical Trials; Control Groups; Cytoplasmic Granules; Daily; Data; Development; Dose; Down-Regulation; Enrollment; Epitopes; Equilibrium; Exposure to; Food; Food Hypersensitivity; Funding; Goals; IL2RA gene; IgE; Immediate hypersensitivity; Immune Tolerance; Immune response; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Immunologics; Immunotherapeutic agent; Immunotherapy; Incidence; Infant; Ingestion; Institutes; Intervention; Life; Measures; Mediator of activation protein; Membrane; Natural History; Oral; Patients; Pattern; Peanuts - dietary; Peripheral; Phenotype; Population; Protocols documentation; Public Health; Randomized; Reaction; Reporting; Research Personnel; Resolution; Risk; Salivary; Serum; Study Subject; Symptoms; T-Lymphocyte; Testing; Time; United States; Work; base; cohort; concept; cytokine; desensitization; egg; food allergen; insight; mast cell; novel; oral tolerance; programs; prospective; response

DESCRIPTION (provided by applicant): Oral tolerance to foods normally develops during the first few years of life. An aberration of oral tolerance, food allergy, occurs in 6% of children and 3.5% of adults in the United States. Egg and peanut allergy are two of the most common food allergies occurring in 1.5% and 1% of young children, respectively. Interestingly, approximately 50% of young children with egg allergy then develop oral tolerance to egg by age 5 years, while only 20% of young children develop oral tolerance to peanuts by age 5 years. We propose to utilize a form of treatment, oral immunotherapy (OIT) to investigate and possibly hasten the development of oral tolerance to eggs and peanuts. This application is based on our data that allergen-specific OIT will desensitize and possibly tolerize egg-allergic and peanut-allergic subjects. Our hypothesis is that instituting egg and peanut OIT early after development of egg or peanut allergy will clinically desensitize both groups of patients by altering basophil/mast cell reactivity and will cause clinical tolerance to develop because of the activity of specific T regulatory cells for egg and peanut. This study will provide new insights into the natural history of the egg- and peanut-specific cellular and humoral immune responses and oral tolerance. This proposal is based on our preliminary studies that have examined the effects of OIT on egg and peanut allergies. Our approach will be to enroll two cohorts of subjects and controls early in life who have egg allergy or peanut allergy both soon after their development and treat them with either egg or peanut OIT in a randomized, blinded OIT protocol. Utilizing an already established protocol of study subjects entering a proof of concept study funded by the Food Allergy Project, we will study the basophil/mast cell reactivity, antigen-specific T cell responses and mucosal and systemic humoral immune responses in these subjects. This grant application is not intended to support the clinical trial portion of this work but only the mechanistic studies as described. Our specific aims are the following: (1) determine if the development of the desensitized state to egg and peanut is associated with the down-regulation of mast cells and basophils, (2) determine if the development of clinical tolerance to egg and peanuts is associated with an increase in the T regulatory phenotype of antigen-activated peripheral CD4+ T cells and (3) determine the effect of egg- and peanut-specific mucosal and systemic humoral immune responses on oral tolerance and OIT. The short-term goal of the protocol is to induce a desensitized state to egg and peanut early in the course of treatment that will protect subjects from allergic reactions following accidental egg or peanut ingestions. The long-term goal of the study is to utilize egg and peanut OIT for the induction of clinical and immunologic tolerance to the allergen that will be sustained once the protocol is completed.

描述（由申请人提供）：对食物的口服耐受性通常在生命的头几年发展。在美国，有6％的儿童和3.5％的成年人发生口服耐受性，食物过敏。卵和花生过敏是分别以1.5％和1％的幼儿发生的两种最常见的食物过敏。 有趣的是，大约50％的卵过敏的幼儿在5岁时对卵产生口服耐受性，而只有20％的幼儿在5岁时会出现对花生的口服耐受性。我们建议利用一种治疗形式，口服免疫疗法（OIT）来调查并可能加快对卵和花生的口服耐受性的发展。该应用基于我们的数据，该数据是过敏原特异性OIT将脱敏并可能耐受卵过敏和花生过敏性受试者。我们的假设是，卵或花生过敏后早期提早建立卵和花生OIT将通过改变嗜碱性粒细胞/肥大细胞反应性来在临床上脱敏两组患者，并会导致临床耐受性，因为卵和花生的特定T调节细胞的活性。这项研究将提供有关卵和花生特异性细胞和体液免疫反应以及口服耐受性的自然历史的新见解。该提议基于我们的初步研究，该研究检查了OIT对卵和花生过敏的影响。我们的方法是在生命的早期招募两个受试者和对照组，他们在发育后不久就会接受卵过敏或花生过敏，并用随机的，盲目的OIT方案中的鸡蛋或花生OIT对其进行处理。利用已经建立的研究对象的方案，该方案进入了由食物过敏项目资助的概念验证研究，我们将研究这些受试者中的嗜碱性粒细胞/肥大细胞反应性，抗原特异性T细胞反应以及粘膜和全身性体液免疫反应。 该赠款的应用并非旨在支持这项工作的临床试验部分，而仅支持所述的机械研究。 Our specific aims are the following: (1) determine if the development of the desensitized state to egg and peanut is associated with the down-regulation of mast cells and basophils, (2) determine if the development of clinical tolerance to egg and peanuts is associated with an increase in the T regulatory phenotype of antigen-activated peripheral CD4+ T cells and (3) determine the effect of egg- and peanut-specific mucosal and口服耐受性和OIT的全身性体液免疫反应。 该方案的短期目标是在治疗过程的早期对卵和花生诱导脱敏状态，以保护受试者免受意外卵或花生摄入后的过敏反应。该研究的长期目标是利用鸡蛋和花生OIT来诱导一旦协议完成，对过敏原诱导了对过敏原的临床和免疫耐受性。