Immunological Basis of Egg Allergy

鸡蛋过敏的免疫学基础

• 批准号: 7086816
• 负责人: Anna Halina Nowak-Wegrzyn
• 金额: $ 12.87万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086816
• 关键词: adolescence (12-20); antibody specificity; atopic dermatitis; child (0-11); clinical research; dietary constituent; egg proteins; epitope mapping; feces analysis; food hypersensitivity; gastrointestinal absorption /transport; heat; human subject; immune response; immunogenetics; immunoglobulin E; nutrition related tag; patient oriented research

DESCRIPTION (provided by applicant): My immediate goal is to acquire skills necessary for an independent career in patient-oriented research. I need training in design and conduct of patient-oriented research as well in immunology laboratory techniques. My long-term objectives are to stablish myself as an investigator in the field of novel therapies for food allergy. I am confident that at Mount Sinai I am in the nurturing environment committed to my success. I will receive highest-quality mentoring from Dr. Hugh A. Sampson and will have strong support from the Food Allergy Laboratory with access to the state-of-the-art equipment. Clinical Research Training Program to develop solid skills in responsible conduct, design, and analysis of clinical research. Egg allergy is one of the most common food allergies in children. Allergic reactions are more frequently caused by egg white than by egg yolk proteins and ovomucoid is the dominant allergen. Previous studies have demonstrated that children with persistent egg allergy have significantly higher concentrations of IgE-anti-ovomucoid antibodies than those who develop tolerance to egg and those with high IgE-binding activity to pepsin-treated ovomucoid are unlikely to outgrow egg white allergy. We propose to test the following hypotheses: 1. Specific Aim # 1: Test the hypothesis that egg-allergic children who can ingest extensively heated (baked) egg proteins without experiencing allergic symptoms lack IgE antibodies to sequential egg epitopes compared with children that react to extensively heated egg and possess IgE antibodies to sequential egg epitopes. Children with egg allergy will be challenged to baked products containing cooked egg proteins. Challenge outcome will be compared to epitope recognition. Children tolerating egg in baked goods will be randomized to receive egg-free or egg containing diet, and monitored for 48 months. Egg protein- and epitope- specific IgE and IgG antibodies, intestinal permeability, and growth will be monitored. 2. Specific Aim # 2: Test the hypothesis that children with more diverse egg IgE epitope recognition patterns have functional consequences on effector cells resulting in more severe reactions and more persistent egg allergy. IgE and IgG antibody avidity and epitope specificity to the two major egg white allergens (ovomucoid and ovalbumin) will be monitored on a yearly basis by peptide array in 90 patients with IgE-mediated egg allergy over 48 months and will be correlated with clinical reactivity to egg determined by double-blinded placebo controlled egg challenges. Antibody avidity will be assessed with thiocyanate disruption. The effector function of IgE antibodies will be assessed by basophil release test with the use of passively sensitized FceRI-transfected rat basophil leukemia cell line stimulated with native and heat-inactivated egg proteins. 3. Specific Aim# 3: Test the hypothesis that egg-specific IgE antibodies facilitate uptake of egg allergen in the gastrointestinal tract and that the concentration of fecal egg-lgE antibody correlates with intestinal permeability and clinical reactivity to egg in children with egg allergy. We postulate that egg-allergic children have anti-egg IgE antibodies detectable in stool, and that luminal anti-egg IgE antibodies facilitate the uptake of egg allergen, resulting in clinical symptoms and increased intestinal permeability. Stool samples will be obtained prior to and following each oral egg challenge (at multiple time points over 48 months) in children participating in a clinical trial described in Aim # 1. Total and egg-specific IgE, egg-lgE and egg-specific IgG will be determined in each stool sample and correlated with clinical outcome of the oral egg challenge. Intestinal permeability will be tested prior to baseline egg challenges in all children participating in Aim # 1 and following oral egg challenges in a smaller subset of patients. Intestinal permeability will also be measured at 3 and 12 months, and correlated with oral egg challenge outcome, fecal and serum anti-egg IgE and anti-egg IgG antibody levels.

描述(由申请者提供)：我的近期目标是获得在以病人为中心的研究中独立发展所必需的技能。我需要在设计和进行以病人为中心的研究以及免疫学实验室技术方面的培训。我的长期目标是成为食物过敏新疗法领域的一名研究人员。我相信，在西奈山，我正处于致力于我成功的培育环境中。我将得到休·A·桑普森博士最高质量的指导，并将得到食物过敏实验室的大力支持，获得最先进的设备。临床研究培训计划，培养负责任地进行、设计和分析临床研究的扎实技能。鸡蛋过敏是儿童最常见的食物过敏之一。过敏反应更多是由蛋清引起的，而不是由蛋黄蛋白引起的，类卵粘蛋白是主要的过敏原。先前的研究表明，与那些对鸡蛋产生耐受性的儿童相比，患有持续性鸡蛋过敏的儿童的IgE抗卵粘蛋白抗体浓度明显更高，那些对胃酶治疗的卵粘蛋白具有高IgE结合活性的儿童不太可能长大后摆脱蛋清过敏。 我们建议检验以下假设： 1.具体目标1：测试这样一种假设，即与对高温鸡蛋有反应并对连续鸡蛋表位具有IgE抗体的儿童相比，可以摄取高度加热(烘焙)的鸡蛋蛋白而不会出现过敏症状的鸡蛋过敏儿童缺乏针对连续鸡蛋表位的IgE抗体。鸡蛋过敏的儿童将被要求食用含有煮熟的鸡蛋蛋白的烘焙产品。挑战结果将与表位识别进行比较。耐受烘焙食品中鸡蛋的儿童将随机接受不含鸡蛋或含鸡蛋的饮食，并进行为期48个月的监测。将监测鸡蛋蛋白和表位特异性的IgE和IgG抗体、肠道通透性和生长情况。 2.具体目标2：验证这样一种假设，即具有更多不同鸡蛋IgE表位识别模式的儿童对效应细胞具有功能性后果，从而导致更严重的反应和更持久的鸡蛋过敏。多肽阵列将每年监测90例IgE介导的鸡蛋过敏患者48个月内对两种主要蛋清过敏原(类卵粘蛋白和卵清蛋白)的IgE和IgG抗体亲和力和表位特异性，并将与双盲安慰剂对照鸡蛋挑战所确定的临床鸡蛋反应性相关联。抗体亲和力将通过硫氰酸盐破坏进行评估。用天然和热灭活的卵蛋白刺激被动致敏的FceRI转基因大鼠嗜碱粒细胞白血病细胞株，通过嗜碱性粒细胞释放试验评价IgE抗体的效应功能。 3.具体目标#3：检验鸡蛋特异性IgE抗体促进鸡蛋过敏原在胃肠道中的吸收，以及鸡蛋过敏儿童粪便中鸡蛋-IgE抗体浓度与肠道通透性和临床对鸡蛋的反应性相关的假设。 我们推测，鸡蛋过敏的儿童在粪便中可检测到抗鸡蛋IgE抗体，并且管腔抗鸡蛋IgE抗体有助于鸡蛋过敏原的摄取，导致临床症状和肠道通透性增加。将在每次口服鸡蛋挑战之前和之后(在超过48个月的多个时间点)采集参加Aim#1所述临床试验的儿童的粪便样本。将在每个粪便样本中检测总的和鸡蛋特异性的IgE、鸡蛋特异性IgE和鸡蛋特异性免疫球蛋白，并与口服鸡蛋挑战的临床结果相关联。在所有参与AIM#1的儿童和较小一部分患者的口服鸡蛋挑战之后，将在基线鸡蛋挑战之前测试肠道通透性。还将在3个月和12个月时测量肠道通透性，并与口服卵子激发结局、粪便和血清抗卵IgE和抗卵IgG抗体水平相关。