Towards the identification of biomarkers for pediatric milk allergy

项目摘要 牛奶过敏是最常见的儿科食物过敏之一，在美国约有2%的幼儿受到影响。 美国1，2，其患病率继续增加3。虽然牛奶过敏通常是 在以后的生活中，它仍然会造成很大的健康风险，因为很难避免所有含乳制品， 意外摄入是常见的。牛奶过敏反应可能非常严重，估计 导致高达13%的致命食物过敏反应4.牛奶过敏的诊断具有挑战性;测试 依赖于检测牛奶过敏原特异性IgE抗体有很高的假阳性率，和非- 假阴性率可以忽略不计。食物挑战为临床提供了最准确的诊断工具， 需要大量的资源和训练有素的工作人员，以可接受的风险进行，这并不总是 在控制良好的研究环境之外。为了改善对牛奶和其他食物过敏的诊断， 需要更好地了解潜在的疾病机制。此外，牛奶过敏的发生率 这种过敏依赖于患者，在某些情况下，这种过敏在成年后仍然存在。除了牛奶- 特异性IgE滴度，这是不可靠的准确预测食物挑战的结果，没有可用的 生物标志物，以评估患者是否会在未来几个月内摆脱过敏，以及他们何时可以开始安全地 摄入乳制品或生牛奶。由于已知CD 4 T细胞在介导食物过敏中起关键作用5，因此我们的中枢神经系统 假设是，研究在患有过敏症的人群中牛奶过敏原特异性T细胞的频率和表型， 不同的疾病表现将定义疾病状态和耐受进展的分子标志物， 并且该信息可用于开发改进的和新的诊断测试。因此我们 建议全面定义来自牛奶过敏原的T细胞表位（目标1），并将其用作试剂， 确定来自具有不同临床表现的供体的抗原特异性T细胞的表型（目的2）， 以及追踪疾病过程中抗原特异性T细胞的纵向发育（目的3）。通过 比较和对比本项目中鉴定的牛奶过敏原特异性T细胞的表型标志物， 真菌，蟑螂和小鼠过敏原特异性T细胞在项目1和3中定义，我们将确定 过敏原特异性T细胞的致病特征，其特异于牛奶（或更广泛的食物）过敏 或与其他过敏原共享。

PROJECT SUMMARY Cow’s milk allergy is among the most common pediatric food allergies, affecting about 2% of young children in the United States 1, 2, and its prevalence continues to increase 3. Although milk allergy is commonly outgrown later in life, it still poses a great health risk as avoidance of all dairy-containing products is difficult and accidental ingestion is common. Cow’s milk allergic reactions can be very severe, and are estimated to be responsible for up to 13% of fatal food-induced anaphylaxis 4. Diagnosis of milk allergy is challenging; tests relying on detection of milk allergen-specific IgE antibodies have a high rate of false positives, and a non- negligible rate of false negatives. Food challenges provide the most accurate diagnostic tool in the clinic, but require significant resources and highly trained staff to be carried out with acceptable risk, which is not always available outside of well-controlled research settings. To improve diagnostics of milk and other food allergies, the underlying disease mechanisms need to be better understood. In addition, the rate at which milk allergy is outgrown is patient dependent and in some cases, this allergy is still present in adulthood. Aside from milk- specific IgE titers, which are not reliably accurate in predicting food challenge outcomes, there are no available biomarkers to assess if a patient will outgrow their allergy in coming months and when they can begin to safely ingest dairy or raw milk. As CD4 T cells are known to play a key role in mediating food allergy 5, our central hypothesis is that studying the frequency and phenotype of milk allergen-specific T cells in cohorts with different disease manifestations will define molecular markers of disease status and progression to tolerance, and this information could be utilized for developing improved and new diagnostic tests. Accordingly, we propose to comprehensively define T cell epitopes from milk allergens (Aim 1) and use these as reagents to determine the phenotype of antigen-specific T cells from donors with different clinical manifestations (Aim 2), as well as track the longitudinal development of antigen-specific T cells during the disease course (Aim 3). By comparing and contrasting phenotypic markers of milk allergen-specific T cells identified in this project with fungal, cockroach and mouse allergen-specific T cells defined in Projects 1 and 3, we will determine pathogenic features of allergen-specific T cells that are either specific to milk (or more broadly food) allergies or shared across other allergens.