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）：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。花生过敏是1％的幼儿中最常见的食物过敏之一，是致命食品过敏反应的主要原因。到5岁时，只有20％的幼儿会对花生产生口腔耐受性。我们建议利用疗法，抗Ige（Omalizumab）和花生口服免疫疗法（OIT）的组合来研究并可能加快对花生的口服耐受的发展。 该应用程序基于我们的工作数据，以及其他特定于过敏原的OIT将脱敏并可能耐受花生过敏的受试者。该提议的长期目标和意义是更好地了解对食品的口服耐受性的发展。我们的方法是研究这些受试者在抗IGE和PEANUT OIT上的嗜碱性/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，通过开始使用抗IGE进行治疗，然后开始花生OIT，我们将通过改变嗜碱性/肥大细胞反应性来在临床上脱敏患者，并由于过敏原特异性T调节细胞的活性而导致最终的临床耐受性。 先前对我们研究人员的花生OIT的研究表明，在OIT的前6-9个月中，受试者脱敏花生，并将忍受多达15种没有症状的花生。对于超过2 1/2年的OIT治疗的那些受试者，现在超过50％在临床上耐受花生的耐受性。 该提案附带的临床研究是杜克大学的一项前瞻性试验，其花生过敏性受试者。我们将注册10名患者。这项研究将包括4个阶段：免疫疗法前的抗IGE治疗，修改后的高峰日，4个月的积聚期和每日家庭维护阶段，最终剂量为8000mg花生粉（〜50％花生蛋白）。抗IGE将在最初修改的急流日（S）之前4个月开始，并在达到每日维持剂量的花生OIT（8 gms）（总抗IGE时间10个月）后持续一个月。重要的是，我们将在开始使用抗IGE的开始时进行以下机械研究，然后在开始花生OIT之前，然后以各种适当的时间间隔来确定抗Ige和Peanut OIT对免疫变化的个体和集体贡献。 我们想建立一种免疫治疗方法，该方法将下调食物特定的免疫反应，降低对数百万美国人遭受食物过敏的食物的意外暴露的过敏反应的风险，并产生最终会导致真正的临床耐受性的治疗方法。这项研究将提供有关花生特异性细胞和体液免疫反应和口服耐受性的新见解。