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: 8449783
• 负责人: A. Wesley Burks
• 金额: $ 9.61万
• 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/8449783
• 关键词: Combined; Peanut; Oral; Immunotherapy; Anti

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最初几年内形成。在美国，6% 的儿童和 3.5% 的成人出现口腔耐受性异常，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，也是致命食物过敏反应的主要原因。只有 20% 的幼儿会在 5 岁时形成对花生的口服耐受性。我们建议采用抗 IgE（奥马珠单抗）和花生口服免疫疗法 (OIT) 的组合来研究并可能加速花生口服耐受的发展。 该应用程序基于我们的工作数据和其他数据，即过敏原特异性 OIT 将使花生过敏受试者脱敏并可能耐受。该提案的长期目标和意义是更好地了解口服食物耐受性的发展。我们的方法是研究这些受试者对抗 IgE 和花生 OIT 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，我们将通过改变嗜碱性粒细胞/肥大细胞反应性在临床上使患者脱敏，并且由于过敏原特异性 T 调节细胞的活性，最终导致临床耐受性的发展。 我们的研究小组之前对花生 OIT 的研究表明，在 OIT 的前 6 - 9 个月内，受试者对花生变得不敏感，并且可以耐受多达 15 颗花生而不会出现症状。对于那些接受 OIT 治疗超过 2 1/2 年的受试者，超过 50% 现在对花生具有临床耐受性。 该提案所附的临床研究是杜克大学对花生过敏受试者进行的一项前瞻性试验。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、修改后的高峰日、4 个月的积累期以及每日家庭维持阶段，最终剂量为 8000 毫克花生粉（约 50%）花生蛋白）。抗IgE将在最初修改高峰日之前4个月开始，并在达到每日花生OIT维持剂量（8克）后持续1个月（总抗IgE时间10个月）。重要的是，我们将在抗 IgE 治疗开始时、开始花生 OIT 之前以及此后的不同适当时间间隔进行以下机制研究，以确定抗 IgE 和花生 OIT 对免疫变化的个体和集体贡献。 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发生过敏反应的风险，并开发出一种最终的治疗方法，以产生真正的临床耐受性。这项研究将为花生特异性细胞和体液免疫反应以及口服耐受性提供新的见解。