INDUCTION OF FOOD ALLERGY BY INTESTINAL DENDRITIC CELLS

描述（由申请人提供）：在西方化的世界，食物过敏的患病率正在上升；然而，导致这种潜在严重疾病发展的煽动因素仍然未知。食物过敏性疾病的发病机制与所有过敏性疾病一样，取决于Th2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Th2细胞和IgE的诱导取决于树突状细胞（DC）介导的敏化阶段。本应用程序的主要目的是了解胃肠道（GI） DC和病毒在食物过敏发展中的作用，基于先前在肺部的发现，呼吸道病毒启动DC依赖途径，最终导致特应性疾病的发展。在肺部，病毒感染诱导DC上表达IgE高亲和力受体（FceRI）。这种受体的交联导致Th2细胞释放一种化学引诱剂。在病毒感染期间暴露于非病毒抗原诱导IgE对抗非病毒抗原。因此，这些数据支持了IgE介导的DC上FceRI交联导致Th2细胞募集和分化，从而启动针对无害环境抗原的IgE生产的假设。如果这种机制在胃肠道中起作用，就可以解释针对食物过敏原的IgE的产生和食物过敏的发生。我们发现，胃肠道病毒感染在胃肠道DC上诱导FceRI，其方式与我们在肺部看到的相似。因此，为了验证GI病毒感染启动dc依赖通路最终导致食物过敏的假设，我们提出以下两个具体目标：目的1 .确定GI树突状细胞FceRI交联对树突状细胞功能的影响。在此目的中，将利用体外方法来探索GI DC上的FceRI交联是否会导致Th2化学引诱剂的释放，并使T细胞向Th2表型倾斜。目的二世。表征GI树突状细胞FceRI表达与IgE之间的联系。在这个目标中，体内方法将被用来探索胃肠道DC FceRI在募集和Th2细胞发育中的作用，以及在胃肠道病毒感染期间对抗食物过敏原的IgE的产生。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，在动物模型中可以开发出治疗或预防食物过敏的新疗法。

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.