Towards the identification of biomarkers for pediatric milk allergy

项目总结 牛奶过敏是最常见的儿科食物过敏之一，影响约2%的幼儿。 美国1、2，而且其患病率还在继续增加3.虽然牛奶过敏通常不会增长 在以后的生活中，它仍然构成巨大的健康风险，因为避免所有含乳制品是困难的，并且 意外摄入是很常见的。牛奶过敏反应可能非常严重，据估计 高达13%的致命性食物过敏反应的责任4.牛奶过敏的诊断具有挑战性；检测 依赖于检测牛奶过敏原特异性IgE抗体有很高的假阳性率，而非 假阴性率可以忽略不计。食物挑战提供了临床上最准确的诊断工具，但 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可用。为了提高牛奶和其他食物过敏的诊断水平， 需要更好地了解潜在的疾病机制。此外，牛奶过敏的比率是 Out取决于患者，在某些情况下，这种过敏反应在成年后仍然存在。除了牛奶- 在预测食物挑战结果方面不可靠地准确的特定IgE效价，没有可用的 用于评估患者是否会在接下来的几个月内摆脱过敏以及何时可以开始安全治疗的生物标记物 摄入奶制品或生奶。由于已知CD4T细胞在调节食物过敏中起关键作用，我们的中枢 假说是研究牛奶过敏原特异性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性进展的分子标记， 这些信息可以用来开发改进的和新的诊断测试。因此，我们 建议全面定义牛奶过敏原的T细胞表位(目标1)，并将其用作试剂 确定具有不同临床表现的供者的抗原特异性T细胞表型(目标2)， 以及跟踪疾病过程中抗原特异性T细胞的纵向发展(目标3)。通过 将本项目中确定的牛奶过敏原特异性T细胞的表型标志物与 项目1和3中定义的真菌、蟑螂和小鼠过敏原特异性T细胞，我们将确定 牛奶(或更广泛的食物)过敏的过敏原特异性T细胞的致病特征 或在其他过敏原之间共享。

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.