Mechanistic Core

机械学核心的广泛目标如下：1)继续从前一个授权期开始进行机械学研究，旨在确定食物过敏和“自然”或免疫疗法诱导的耐受性发展的潜在机制，2)为这项新提案中的每个项目提供实现这些目标的平台，以及3)利用最初授权期收集的信息来建立新的假设和提供新的研究途径。在最初的授予期间，我们在5个地点建立了统一的可重复技术，允许研究致敏和T细胞激活，并评估耐受性的发展。有几个发现让我们质疑以前的一些教条，包括这样一个事实，即大量对牛奶和鸡蛋过敏的儿童在很小的时候就已经对花生过敏，GATA-3转录因子在人类过敏反应中的作用可能比之前认为的要小，这些患者中IL-4(以及随后的IgE)很可能来自非T细胞来源。目前的建议旨在继续 目前的研究集中在T细胞和APC在变态反应致敏和耐受中的作用，以及扩大对嗜碱性粒细胞在这一过程中的作用的研究。此外，我们现在计划专门探索GATA-3在T细胞和非T细胞中的表达和调节，利用前面描述的免疫学参数，启动试图将食物过敏的表达与特应性皮炎、哮喘或过敏性鼻炎和嗜酸性食管炎相关联的研究，最后使用微阵列 确定特应性疾病的新途径和标记物、疾病解决和耐受性以及疾病表型的不同表达(AD与EE)的方法。这些正在进行的新研究将在人类研究的基础上加强我们对特应性疾病发病机制的理解。

The broad goals of the Mechanistic Core are the following: 1) to continue mechanistic studies from the prior granting period aimed at defining the mechanisms underlying the development of food allergy and "natural" or immunotherapeutically-induced tolerance, 2) to provide a platform for every project within this new proposal to achieve these goals and 3) to utilize the information gathered during the initial granting period to establish new hypotheses and provide new avenues for investigation. During the initial granting period we established uniform reproducible technology across 5 sites allowing for the study of sensitization and T-cell activation, and assessment of the development of tolerance. There were several findings that caused us to question some of the previous dogma including the fact that a large cohort of milk and egg allergic children were already sensitized to peanut at an early age, that the GATA-3 transcription factor may play less of a role in allergic sensitization in humans than previously thought and that there was a high likelihood of a non- T cell origin for IL-4 (and consequent IgE) in these patients. The current proposal seeks to continue the current studies focused on the role of T cells vs. APCs in allergic sensitization and tolerance, as well as expand studies on the role of basophils in this process. In addition, we now plan to specifically explore the expression and regulation of GATA-3 in T and non-T cells, initiate studies attempting to correlate the expression of food allergy as either atopic, i.e. atopic dermatitis, asthma or allergic rhinitis, vs eosinophilic esophagitis using the immunologic parameters previously described, and finally to use a microarray approach to define novel pathways and markers of atopic disease, disease resolution and tolerance and the distinct expression of disease phenotypes (AD vs EE). These ongoing and new studies should enhance our understanding of the pathogenesis of atopic disease based upon human study.