Combined Peanut Oral Immunotherapy and Anti-IgE: Mechanistic Studies

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形成。在美国，6%的儿童和3.5%的成年人发生口服耐受性异常，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，是致命的食物过敏反应的主要原因。只有20%的幼儿在5岁时会对花生产生口服耐受性。我们建议利用抗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性的发展。 该应用基于我们的工作数据和其他过敏原特异性OIT将脱敏并可能耐受花生过敏受试者的数据。本提案的长期目标和意义是更好地了解口服耐受性的发展。我们的方法将是研究嗜碱性粒细胞/肥大细胞的反应性，抗原特异性T细胞反应和粘膜和全身的体液免疫反应，在这些科目的抗IgE和花生OIT。我们的假设是，通过开始用抗IgE治疗，然后开始花生OIT，我们将通过改变嗜碱性粒细胞/肥大细胞的反应性使患者临床脱敏，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性发展。 我们的研究小组以前对花生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，并且可以耐受多达15个花生而没有症状。对于那些接受OIT治疗超过2 1/2年的受试者，超过50%的受试者现在对花生具有临床耐受性。 本提案所附的临床研究是在杜克大学对花生过敏受试者进行的前瞻性试验。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、改良的高峰日、4个月的建立期和每日家庭维持期，最终剂量为8000 mg花生粉（约50%花生蛋白）。抗IgE将在初始改良高峰日前4个月开始，并在达到花生OIT每日维持剂量（8 g）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之前以及之后的各种适当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疗法，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意外暴露于食物的过敏反应风险，并开发出最终的治疗方法，从而导致真正的临床耐受性。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。

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.