INDUCTION OF FOOD ALLERGY BY INTESTINAL DENDRITIC CELLS

肠树突细胞诱导食物过敏

• 批准号: 7640827
• 负责人: Mitchell H Grayson
• 金额: $ 18.94万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-18 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640827
• 关键词: Adoptive Transfer; Affinity; Allergic; Animal Model; Antibodies; Antigens; Antiviral Agents; Binding; CD4 Positive T Lymphocytes; Cell physiology; Chemotactic Factors; Data; Dendritic Cells; Developed Countries; Development; Disease; Event; Exposure to; Food; Food Hypersensitivity; Gastrointestinal tract structure; Generations; Goals; IgE; IgE Receptors; In Vitro; Infection; Intestines; Knowledge; Link; Lung; Lung diseases; Mediating; Mus; Norovirus; Organ; Pathway interactions; Phase; Phenotype; Play; Prevalence; Process; Production; Recruitment Activity; Role; Signal Transduction; System; T-Lymphocyte; Testing; Th2 Cells; Translating; Viral; Viral Antigens; Virus; Virus Diseases; Work; atopy; base; chemokine; crosslink; cytokine; food allergen; gastrointestinal; gastrointestinal infection; in vivo; innovation; novel; prevent; receptor; receptor expression; respiratory; respiratory virus; response

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.

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，食物过敏疾病的机制取决于 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) 介导的致敏阶段。该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的作用，基于之前在肺部的发现，呼吸道病毒启动了 DC 依赖性途径，最终导致特应性疾病的发展。在肺部，病毒感染诱导 DC 上 IgE 高亲和力受体 (FceRI) 的表达。该受体的交联导致 Th2 细胞化学引诱剂的释放。病毒感染期间接触非病毒抗原会诱导针对非病毒抗原的 IgE。因此，这些数据支持以下假设：DC 上 IgE 介导的 FceRI 交联导致 Th2 细胞的募集和分化，从而启动针对无害环境抗原的 IgE 产生。如果这种机制在胃肠道中发挥作用，就可以解释针对食物过敏原的 IgE 的产生以及食物过敏的发生。我们发现胃肠道病毒感染会在胃肠道 DC 上诱导 FceRI，其方式类似于我们在肺部看到的情况。因此，为了检验胃肠道病毒感染启动 DC 依赖性途径最终导致食物过敏的假设，我们提出以下两个具体目标： 目标 I. 定义胃肠道树突状细胞 FceRI 交联对树突状细胞功能的影响。在这个目标中，将利用体外方法来探索 GI DC 上交联 FceRI 是否会导致 Th2 趋化剂的释放并使 T 细胞偏向 Th2 表型。目标二。表征胃肠道树突状细胞 FceRI 表达与 IgE 之间的联系。在此目标中，将利用体内方法探索 GI DC FceRI 在 Th2 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，可以开发新的疗法来治疗或预防食物过敏。