Combined Peanut Oral Immunotherapy and Anti-IgE: Mechanistic Studies

花生口服免疫疗法与抗 IgE 联合治疗：机制研究

• 批准号: 8320084
• 负责人: A. Wesley Burks
• 金额: $ 18.5万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320084
• 关键词: 5 year old; Address; Adolescent; Adult; Allergens; Allergic; Allergic Reaction; Allergy to peanuts; American; Anaphylaxis; Antigens; Basophils; Blocking Antibodies; CD4 Positive T Lymphocytes; Cells; Child; Clinical; Clinical Research; Clinical Trials; Data; Development; Disease; Dose; Down-Regulation; Enrollment; Epitopes; Equilibrium; Exposure to; Flour; Food; Food Hypersensitivity; Future; Goals; Home environment; IL2RA gene; IgE; IgG4; Immediate hypersensitivity; Immune; Immune Tolerance; Immune response; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; Immunotherapeutic agent; Immunotherapy; Individual; Interleukin-10; Life; Maintenance; Measurable; Measures; Mediator of activation protein; Patients; Peanuts - dietary; Peripheral; Phase; Phenotype; Population; Proteins; Reaction; Regulatory T-Lymphocyte; Research Personnel; Risk; Safety; Salivary; Secretory Immunoglobulin A; Serum; Signal Transduction; Symptoms; T cell response; T-Lymphocyte; Time; United States; Universities; Work; active method; allergic response; anti-IgE; base; cytokine; desensitization; improved; insight; mast cell; novel; novel strategies; omalizumab; oral immunotherapy; oral tolerance; 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. Peanut allergy is one of the most common of the food allergies occurring in 1% of young children and is the leading cause of fatal food anaphylaxis. Only 20% of young children will develop oral tolerance to peanuts by age 5 years. We propose to utilize a combination of treatments, anti-IgE (omalizumab) and peanut oral immunotherapy (OIT) to investigate and possibly hasten the development of oral tolerance to peanuts. This application is based on our data from our work and others that allergen-specific OIT will desensitize and possibly tolerize peanut-allergic subjects. The long term goal and significance of this proposal is to better understand the development of oral tolerance to foods. Our approach will be to study the basophil/mast cell reactivity, antigen-specific T cell responses and mucosal and systemic humoral immune responses in these subjects on anti-IgE and peanut OIT. Our hypothesis is that by beginning treatment with anti-IgE and then starting peanut OIT we will clinically desensitize patients by altering basophil/mast cell reactivity and will cause eventual clinical tolerance to develop because of the activity of allergen-specific T regulatory cells. Previous studies of peanut OIT from our group of investigators show that during the first 6 - 9 months of OIT the subjects become desensitized to peanuts and will tolerate up to 15 peanuts without symptoms. For those subjects on treatment with OIT longer than 2 1/2 years, more than 50% are now clinically tolerant to peanuts. The clinical study this proposal is attached to is a prospective trial at Duke University with peanut-allergic subjects. We will enroll 10 patients. The study will consist of 4 phases: anti-IgE therapy before immunotherapy, a modified rush day(s), a build-up period of 4 months, and a daily home maintenance phase with a final dose of 8000mg peanut flour (~50% peanut protein). The anti-IgE will be started 4 months prior to the initial modified rush day(s) and continued for one month after they have reached the daily maintenance dose of peanut OIT (8 gms) (total anti-IgE time 10 months). Importantly, we will conduct the following mechanistic studies at the beginning of treatment with anti-IgE, prior to starting peanut OIT and then at various appropriate intervals thereafter to determine the individual and collective contribution of anti-IgE and peanut OIT to the immune changes. We want to establish an immunotherapeutic approach that would down-regulate food specific immune responses, lower the risk of allergic reactions to accidental exposure to foods in the millions of Americans who suffer from food allergy and develop an eventual treatment that will cause true clinical tolerance. This study will provide new insights into peanut-specific cellular and humoral immune responses and oral tolerance.

描述(由申请人提供)：口腔对食物的耐受性通常在生命的最初几年发展起来。在美国，6%的儿童和3.5%的成年人会出现一种口服耐受性异常，即食物过敏。花生过敏是最常见的食物过敏之一，发生在1%的幼儿中，是致命性食物过敏的主要原因。到5岁时，只有20%的幼儿会对花生产生口服耐受性。我们建议联合使用抗IgE(奥马珠单抗)和花生口服免疫疗法(OIT)来研究并可能加速花生口服耐受性的发展。这项应用是基于我们的工作和其他人的数据，过敏原特异性OIT将使花生过敏对象脱敏，并可能耐受。这项建议的长期目标和意义是为了更好地了解口腔对食物耐受性的发展。我们的方法将是研究这些受试者在抗IgE和花生籽粒中的嗜碱性粒细胞/肥大细胞反应性、抗原特异性T细胞反应以及粘膜和全身体液免疫反应。我们的假设是，通过开始抗IgE治疗，然后开始花生OIT，我们将在临床上通过改变嗜碱粒/肥大细胞的反应性来使患者脱敏，并将由于过敏原特异性T调节细胞的活性而导致最终的临床耐受。我们研究组以前对花生OIT的研究表明，在OIT的前6-9个月，受试者对花生变得不敏感，可以耐受多达15颗没有症状的花生。对于那些接受OIT治疗超过两年半的受试者，现在有超过50%的人对花生有临床耐受性。这项建议所附的临床研究是杜克大学的一项针对花生过敏受试者的前瞻性试验。我们将招收10名患者。研究分为4个阶段：免疫治疗前的抗-Ig E治疗阶段、改进的高峰日(S)、4个月的积累期和每日家庭维护阶段，最终剂量为8000 mg花生粉(~50%花生蛋白)。抗-Ig E在最初的修改高峰日(S)前4个月开始，在达到花生油每日维持量(8克)后持续1个月(总抗-Ig E时间10个月)。重要的是，我们将在开始使用抗IgE治疗时，在开始花生OIT之前进行以下机制研究，然后在此后不同的适当时间间隔进行以下机制研究，以确定抗IgE和花生OIT对免疫变化的个人和集体贡献。我们希望建立一种免疫治疗方法，下调食物特异性免疫反应，降低数百万患有食物过敏的美国人因意外接触食物而产生过敏反应的风险，并开发出一种最终将导致真正的临床耐受的治疗方法。这项研究将为花生特异的细胞和体液免疫反应和口服耐受性提供新的见解。