INDUCTION OF FOOD ALLERGY BY INTESTINAL DENDRITIC CELLS

描述(申请人提供)：在西化世界，食物过敏的流行正在增加；然而，导致这种潜在严重疾病发展的煽动因素仍不清楚。与所有过敏性疾病一样，食物过敏症的发病机制依赖于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的诱导依赖于树突状细胞(DC)介导的致敏阶段。这项应用的主要目标是了解胃肠道(GI)DC和病毒在食物过敏发展中所起的作用，基于先前在肺部的发现，呼吸道病毒启动DC依赖的途径，最终导致特应性疾病的发展。在肺组织中，病毒感染诱导DC表面高亲和力IgE受体(FceRI)的表达。这种受体的交联导致了一种对Th2细胞的趋化物质的释放。在病毒感染期间暴露于非病毒抗原可诱导抗非病毒抗原的IgE。因此，这些数据支持这样的假设，即IgE介导的FceRI在DC上的交联会导致Th2细胞的募集和分化，启动针对无害环境抗原的IgE产生。如果这一机制在胃肠道中起作用，它将解释为什么产生抗食物过敏原的IgE和食物过敏的发展。我们发现，胃肠道病毒感染会在胃肠道DC上诱导FceRI，其方式与我们在肺中看到的类似。因此，为了验证GI病毒感染启动DC依赖的途径最终导致食物过敏的假设，我们提出了以下两个特定目标：目的I确定GI树突状细胞FceRI交联物对树突状细胞功能的影响。为了达到这个目的，我们将利用体外实验的方法来探索GI DC上的FceRI是否会导致Th2趋化因子的释放，并使T细胞偏向Th2表型。目的II.研究GI树突状细胞FceRI表达与IgE的关系。为了达到这一目的，将利用体内方法来探索GI DC FceRI在Th2细胞的招募和发展中的作用，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，在该模型中，可能会开发新的治疗方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.