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形成。在美国，有6%的儿童和3.5%的成人出现口腔耐受异常，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，是致命的食物过敏反应的主要原因。只有20%的幼儿在5岁之前会对花生产生口服耐受。我们建议利用抗ige （omalizumab）和花生口服免疫治疗（OIT）的联合治疗来研究并可能加速花生口服耐受的发展。这一应用是基于我们的工作数据和其他关于过敏原特异性OIT会脱敏和可能耐受花生过敏受试者的数据。这项建议的长期目标和意义是更好地了解口腔对食物的耐受性的发展。我们的方法将是研究这些受试者的嗜碱性细胞/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治疗，我们将通过改变嗜碱性细胞/肥大细胞的反应性，在临床上使患者脱敏，并最终导致临床耐受性的产生，因为过敏原特异性T调节细胞的活性。我们的研究小组先前对花生油变性的研究表明，在油变性的前6 - 9个月，受试者对花生脱敏，可以耐受多达15颗花生而没有症状。对于那些接受OIT治疗超过2年半的受试者，超过50%的人现在临床上对花生耐受。该提案所附的临床研究是杜克大学对花生过敏受试者的前瞻性试验。我们将招募10名患者。该研究将包括4个阶段：免疫治疗前的抗ige治疗，改进的高峰日，4个月的积累期，以及每日家庭维护阶段，最终剂量为8000mg花生面粉（~50%花生蛋白）。抗ige将在初始修改高峰期前4个月开始，并在达到花生OIT的每日维持剂量（8克）后继续一个月（总抗ige时间为10个月）。重要的是，我们将在抗ige治疗开始时进行以下机制研究，在开始花生OIT之前，然后在各种适当的间隔时间进行研究，以确定抗ige和花生OIT对免疫变化的个体和集体贡献。我们希望建立一种免疫治疗方法，可以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，并最终开发出一种能够产生真正临床耐受性的治疗方法。这项研究将为花生特异性细胞和体液免疫反应和口服耐受性提供新的见解。