Understanding the Mechanism of Mucosal Immunotherapy

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。鸡蛋和花生过敏是两种最常见的食物过敏，分别发生在1.5%和1%的幼儿中。 有趣的是，大约50%的鸡蛋过敏幼儿在5岁时对鸡蛋产生口服耐受性，而只有20%的幼儿在5岁时对花生产生口服耐受性。我们建议利用一种治疗形式，口服免疫疗法（OIT）来研究并可能加速对鸡蛋和花生的口服耐受性的发展。该应用基于我们的数据，即过敏原特异性OIT将使鸡蛋过敏和花生过敏受试者脱敏并可能耐受。我们的假设是，在鸡蛋或花生过敏发生后早期进行鸡蛋和花生OIT，将通过改变嗜碱性粒细胞/肥大细胞反应性使两组患者在临床上脱敏，并由于鸡蛋和花生特异性T调节细胞的活性而导致临床耐受性的发展。这项研究将为鸡蛋和花生特异性细胞和体液免疫反应和口服耐受的自然史提供新的见解。这项建议是基于我们的初步研究，研究了OIT对鸡蛋和花生过敏的影响。我们的方法是招募两组受试者和对照组，他们在发育后不久就对鸡蛋或花生过敏，并在随机、盲法OIT方案中用鸡蛋或花生OIT治疗。利用已经建立的研究方案，研究对象进入由食物过敏项目资助的概念验证研究，我们将研究嗜碱性粒细胞/肥大细胞反应性，抗原特异性T细胞反应和粘膜和全身体液免疫反应在这些科目。 本资助申请并不旨在支持这项工作的临床试验部分，而只是所描述的机制研究。 我们的具体目标如下：（1）确定对鸡蛋和花生的脱敏状态的发展是否与肥大细胞和嗜碱性粒细胞的下调有关，（2）确定对鸡蛋和花生的临床耐受性的发展是否与抗原活化的外周CD 4 + T细胞的T调节表型的增加相关，以及（3）确定鸡蛋和花生对免疫耐受性的影响。特异性粘膜和全身体液免疫应答对口服耐受和OIT的影响。 该方案的短期目标是在治疗过程的早期诱导对鸡蛋和花生的脱敏状态，这将保护受试者在意外摄入鸡蛋或花生后免于过敏反应。该研究的长期目标是利用鸡蛋和花生OIT诱导对过敏原的临床和免疫耐受，一旦方案完成，这种耐受将持续下去。

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. Egg and peanut allergy are two of the most common food allergies occurring in 1.5% and 1% of young children, respectively. Interestingly, approximately 50% of young children with egg allergy then develop oral tolerance to egg by age 5 years, while only 20% of young children develop oral tolerance to peanuts by age 5 years. We propose to utilize a form of treatment, oral immunotherapy (OIT) to investigate and possibly hasten the development of oral tolerance to eggs and peanuts. This application is based on our data that allergen-specific OIT will desensitize and possibly tolerize egg-allergic and peanut-allergic subjects. Our hypothesis is that instituting egg and peanut OIT early after development of egg or peanut allergy will clinically desensitize both groups of patients by altering basophil/mast cell reactivity and will cause clinical tolerance to develop because of the activity of specific T regulatory cells for egg and peanut. This study will provide new insights into the natural history of the egg- and peanut-specific cellular and humoral immune responses and oral tolerance. This proposal is based on our preliminary studies that have examined the effects of OIT on egg and peanut allergies. Our approach will be to enroll two cohorts of subjects and controls early in life who have egg allergy or peanut allergy both soon after their development and treat them with either egg or peanut OIT in a randomized, blinded OIT protocol. Utilizing an already established protocol of study subjects entering a proof of concept study funded by the Food Allergy Project, we will study the basophil/mast cell reactivity, antigen-specific T cell responses and mucosal and systemic humoral immune responses in these subjects. This grant application is not intended to support the clinical trial portion of this work but only the mechanistic studies as described. Our specific aims are the following: (1) determine if the development of the desensitized state to egg and peanut is associated with the down-regulation of mast cells and basophils, (2) determine if the development of clinical tolerance to egg and peanuts is associated with an increase in the T regulatory phenotype of antigen-activated peripheral CD4+ T cells and (3) determine the effect of egg- and peanut-specific mucosal and systemic humoral immune responses on oral tolerance and OIT. The short-term goal of the protocol is to induce a desensitized state to egg and peanut early in the course of treatment that will protect subjects from allergic reactions following accidental egg or peanut ingestions. The long-term goal of the study is to utilize egg and peanut OIT for the induction of clinical and immunologic tolerance to the allergen that will be sustained once the protocol is completed.