Regulatory and effector T cells in oral immunotherapy for food allergy

在这个项目中要检验的主要假设是，当牛奶过敏的人接受口服 免疫疗法(OIT)，诱导乳汁特异性调节性T细胞将预测那些 达到最完整、最持久的临床耐受性。为了检验这一假设，我们建议 招募60名对牛奶过敏的儿童和成年人(15岁)，他们长大后很可能不会对牛奶过敏 而不需要任何干预。这些患者将以2：1的比例随机接受任何一种积极的治疗 用牛奶燕麦或安慰剂治疗。他们将接受三次口服牛奶的挑战(安慰剂组将 只有两个挑战)在治疗前确定他们的临床敏感性，在达到 大约三个月，如果他们变得不那么敏感，在三个月的避税之后再次出现。在……里面 通过这种方式，我们期望定义以下群体：1.未能改进或无法达到维护；2.改进 但避免后复发；3.实现更持久的宽容。我们将把这些临床结果与 CD4T细胞亚群的频率和功能的变化，包括那些产生细胞因子(T)的亚群 效应器)，以及那些由其特定蛋白(CD25，FoxP3)的表达调控定义的基因和 而不是其他T细胞(CD127)--以及它们抑制其他T细胞的功能。我们还将研究 OIT中T细胞亚群基因表达的变化以探讨OIT的其他潜在机制 好的。我们将尝试检验这一假设，即特定T细胞亚群数量的扩大，例如 调节亚集的出现是将更多多样性的T细胞整合到该亚集中的结果 检查不同T细胞亚群之间的亲缘关系。最后，我们将努力定义具体的 两种主要牛奶过敏原的区域，可被人类T细胞识别并产生高度特异性 将促进牛奶过敏原特异性T细胞在任何免疫学中的研究的试剂(II类四聚体) 可能对其有用的疾病。

The primary hypothesis to be tested in this project is when milk allergic individuals undergo oral immunotherapy (OIT), the induction of milk-specific regulatory T cells will predict those individuals who achieve the most complete and lasting clinical tolerance. In order to test this hypothesis, we propose to recruit 60 milk allergic children and adults (>15 years) who are very unlikely to outgrow their milk allergy without an intervention. These individuals will be randomized in a 2:1 ratio to receive either active treatment with milk OIT or placebo treatment. They will undergo three oral challenges to milk (the placebo group will have only two challenges) to define their clinical sensitivity before treatment, after reaching maintenance for about three months, and - if they become less sensitive - again after a three month period of avoidance. In this way, we expect to define groups who: 1. fail to improve or are unable to reach maintenance; 2. Improve but relapse after avoidance; 3. Achieve more lasting tolerance. We will compare these clinical outcomes to changes in the frequency and function of CD4 T cell subsets, including those that produce cytokines (T effectors), and those that are regulatory - defined by their expression of specific proteins (CD25, FoxP3) and not others (CD127) - as well as by their functional capacity to suppress other T cells. We will also study global gene expression changes in T cell subsets during OIT to investigate other potential mechanisms of OIT. We will attempt to test the hypothesis that an expansion in numbers of a specific T cell subset, such as the regulatory subset, occurs as a result of incorporating a greater diversity of T cells into that subset and examine the kinship between different T cell subsets. Finally, we will invest in an effort to define the specific regions of two major milk allergens that are recognized by human T cells and develop highly specific reagents (class II tetramers) that will advance the study of milk allergen specific T cells in any immunological disease for which it might be useful.