Understanding the Mechanism of Mucosal Immunotherapy

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。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%的对鸡蛋过敏的幼儿在5岁时对鸡蛋产生口服耐受，而只有20%的幼儿在5岁时对花生产生口服耐受。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的发展。这一应用是基于我们的数据，即过敏原特异性OIT会使鸡蛋过敏和花生过敏的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，会通过改变嗜碱性细胞/肥大细胞的反应性，在临床上使两组患者脱敏，并且由于特异性T调节细胞对鸡蛋和花生的活性，会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。这个建议是基于我们对油脂对鸡蛋和花生过敏的影响的初步研究。我们的方法是招募两组早期对鸡蛋或花生过敏的受试者和对照组，他们在发育后不久就对鸡蛋或花生过敏，并在随机、盲法的油脂治疗方案中使用鸡蛋或花生油脂治疗。利用已经建立的研究对象方案，进入由食物过敏项目资助的概念验证研究，我们将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。这项拨款申请并不打算支持这项工作的临床试验部分，而只是支持所描述的机制研究。我们的具体目标如下:(1)确定发展的麻木状态鸡蛋和花生与肥大细胞和嗜碱粒细胞的下调,(2)确定临床宽容蛋和花生的发展与提高T监管antigen-activated外围CD4 + T细胞的表型和(3)确定蛋的效果,针对花生粘膜和系统性口服宽容和OIT体液免疫反应。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，以保护受试者在意外摄入鸡蛋或花生后不会发生过敏反应。该研究的长期目标是利用鸡蛋和花生油脂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.