INDUCTION OF FOOD ALLERGY BY INTESTINAL DENDRITIC CELLS

描述（由申请人提供）：在西方世界，食物过敏的患病率正在增加;然而，导致这种潜在严重疾病发展的诱发因素仍然未知。与所有过敏性疾病一样，食物过敏性疾病的机制取决于Th 2细胞的发育和针对食物过敏原的IgE抗体的产生。抗原特异性Th 2细胞和IgE的诱导依赖于树突状细胞（DC）介导的致敏阶段。本申请的主要目标是基于先前在肺中的发现来理解胃肠道（GI）DC和病毒在食物过敏发展中的作用，其中呼吸道病毒启动DC依赖性途径，最终导致特应性疾病的发展。在肺中，病毒感染诱导DC上IgE的高亲和力受体（FceRI）的表达。该受体的交联导致Th 2细胞的化学引诱物的释放。在病毒感染期间暴露于非病毒抗原诱导针对非病毒抗原的IgE。因此，这些数据支持DC上IgE介导的FceRI交联导致Th 2细胞的募集和分化，从而启动针对无害环境抗原的IgE产生的假设。如果这种机制在胃肠道中起作用，它将解释针对食物过敏原的IgE的产生和食物过敏的发展。我们已经发现，GI病毒感染诱导GI DC上的FceRI，其方式与我们在肺中看到的相似。因此，为了验证GI病毒感染启动DC依赖性途径最终导致食物过敏的假设，我们提出了以下两个具体目标：定义GI树突细胞FceRI交联对树突细胞功能的影响。在该目的中，将利用体外方法来探索GI DC上的交联FceRI是否导致Th 2化学引诱物的释放并使T细胞偏向Th 2表型。Aim II.表征GI树突细胞FceRI表达与IgE之间的联系。在该目的中，将利用体内方法来探索GI DC FceRI在Th 2细胞的募集和发育中的作用，以及在GI病毒感染期间产生针对食物过敏原的IgE。这些研究的相关性在于，它们提供了有关食物过敏发生机制的重要知识。此外，这些研究为动物模型提供了基础，在该动物模型中可以开发新的疗法来治疗或预防食物过敏。

DESCRIPTION (provided by applicant): The prevalence of food allergy is increasing in the westernized world; however, the inciting factors leading to the development of this potentially severe disease remain unknown. The mechanism of food allergy disease, like all allergic disease, depends upon the development of Th2 cells and production of IgE antibodies against food allergens. Induction of both antigen-specific Th2 cells and IgE depends upon a sensitization phase mediated by dendritic cells (DC). The primary goal of this application is to understand the role gastrointestinal (GI) DC and viruses play in the development of food allergies, based upon previous findings in the lung where respiratory virus initiated a DC-dependent pathway culminating in the development of atopic disease. In the lung, viral infection induced expression of the high affinity receptor for IgE (FceRI) on DC. Cross-linking of this receptor led to release of a chemoattractant for Th2 cells. Exposure to a non-viral antigen during the viral infection induced IgE against the non-viral antigen. Therefore, these data support the hypothesis that IgE- mediated cross-linking of FceRI on DC leads to recruitment and differentiation of Th2 cells initiating IgE production against innocuous environmental antigens. If this mechanism operates in the GI tract, it would explain the production of IgE against food allergens and the development of food allergy. We have found that a GI viral infection induces FceRI on GI DC, in a manner similar to what we saw in the lung. Therefore, to test the hypothesis that GI viral infection initiates a DC-dependent pathway culminating in the development of food allergy, we propose the following two specific aims: Aim I. Define the effect of GI dendritic cell FceRI cross-linking on dendritic cell function. In this aim in vitro approaches will be utilized to explore whether cross-linking FceRI on GI DC leads to release of a Th2 chemoattractant and skews T cells towards a Th2 phenotype. Aim II. Characterize the link between GI dendritic cell FceRI expression and IgE. In this aim in vivo approaches will be utilized to explore the role of GI DC FceRI in the recruitment and development of Th2 cells, as well as generation of IgE against food allergens during a GI viral infection. The relevance of these studies is that they provide important knowledge on the mechanisms involved in the development of food allergies. Further, these studies provide the basis for an animal model in which new therapies may be developed to treat or prevent food allergy.