Sublingual Immunotherapy for Peanut Allergy

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%的幼儿身上。有趣的是，大约只有20%对花生过敏的幼儿在5岁前会对花生产生口服耐受性。我们建议利用一种治疗形式，舌下免疫疗法(SIT)来研究并可能加速口服花生耐受性的发展。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SILT将使花生过敏对象脱敏，并可能耐受。在此之前，还没有经过精心设计的关于食物过敏的科学严谨的研究。我们的假设是，在食物过敏发生后早期建立花生变应原SILT将通过改变嗜碱性细胞/肥大细胞的反应性而在临床上使患者脱敏，并将由于过敏原特异性T调节细胞的活性而导致临床耐受性的形成。这一建议是基于我们的初步研究，这些研究检查了Sit对患有花生过敏的大龄儿童的影响，以及口服免疫疗法对花生和鸡蛋过敏儿童的影响。我们的方法是招募两组对花生敏感的受试者(花生特异性IgE和GT；7KU/L，有明显的初始症状)；一组在发育后不久(1-5岁)，第二组还没有摆脱花生过敏(6-11岁)，并采用前瞻性随机、盲法狭缝方案对他们进行花生狭缝治疗。我们将研究这些受试者的嗜碱性粒细胞/肥大细胞反应性、抗原特异性T细胞反应以及粘膜和系统体液免疫反应。我们正在结合过敏、免疫学和病理学领域的科学研究人员的专业知识，以及我们由NIH资助的GCRC的资源来进行我们的研究。我们的具体目标是：(1)确定过敏原特异性Sit是否会导致花生过敏幼儿的临床脱敏和耐受，(2)确定对花生的脱敏状态的发展是否与肥大细胞和嗜碱性粒细胞下调有关，(3)确定临床对花生的耐受的发展是否与抗原激活的外周CD4+T细胞T调节表型增加有关，以及(4)确定Sit中花生特异的粘膜和系统体液免疫反应对脱敏和口服耐受的影响。这些研究的完成将为口服耐受和变应原特异性缝隙的细胞和分子作用机制提供新的信息，并为开发新的食物过敏治疗方法提供基础。 公共卫生相关性-项目叙述：该项目旨在开发一种食物过敏的治疗方法。6%-8%的幼儿和4%的成年人会对食物过敏，目前还没有预防性的治疗方法。开发一种治疗方法并了解其作用机制对于未来食物过敏患者的治疗非常重要。

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. Interestingly, approximately only 20% of young children with peanut allergy will develop oral tolerance to peanuts by age five. We propose to utilize a form of treatment, sublingual immunotherapy (SLIT) to investigate and possibly hasten the development of oral tolerance to peanuts. This application is based on data from our work and others that allergen-specific SLIT will desensitize and possibly tolerize peanut-allergic subjects. There have not been well-designed previous studies of SLIT for food allergy that have been scientifically rigorous. Our hypothesis is that instituting peanut allergen SLIT early after development of food allergy will clinically desensitize patients by altering basophil/mast cell reactivity and will cause clinical tolerance to develop because of the activity of allergen- specific T regulatory cells. This proposal is based on our preliminary studies that have examined the effects of SLIT in older children with peanut allergy and of oral immunotherapy in peanut- and egg-allergic children. Our approach will be to enroll two cohorts of subjects who have peanut sensitivity (peanut specific IgE > 7 KU/L and significant initial symptoms); one group soon after their development (ages 1 to 5 years) and the second group who have not outgrown their peanut allergy (ages 6 to 11 years) and treat them with peanut SLIT in a prospective randomized, blinded SLIT protocol. We will study the basophil/mast cell reactivity, antigen-specific T cell responses and mucosal and systemic humoral immune responses in these subjects. We are combining the expertise of scientific investigators from the fields of allergy, immunology and pathology and the resources of our NIH-funded GCRC for our studies. Our specific aims are: (1) Determine if allergen-specific SLIT will cause clinical desensitization and tolerance to develop in peanut allergic young children, (2) Determine if the development of the desensitized state to peanut is associated with the down-regulation of mast cells and basophils, (3) Determine if the development of clinical tolerance to peanuts is associated with an increase in the T regulatory phenotype of antigen-activated peripheral CD4+ T cells and (4) Determine the effect of peanut-specific mucosal and systemic humoral immune responses in SLIT on desensitization and oral tolerance. Completion of the studies will provide new information regarding the cellular and molecular mechanisms of action of oral tolerance and allergen-specific SLIT and provide the foundation for the development of novel treatments for food allergy. PUBLIC HEALTH RELEVANCE - PROJECT NARRATIVE: The project is designed to develop a treatment for food allergy. Food allergy effect 6% - 8% of young children and 4% of adults and there are no current preventive treatment available. The development of a treatment and understanding the mechanism of how it works is important for the future treatment of patients with food allergy.