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）：西方世界的食物过敏的普遍性正在增加；但是，导致这种潜在严重疾病发展的煽动因素仍然未知。与所有过敏性疾病一样，食物过敏疾病的机制取决于Th2细胞的发展以及对食物过敏原的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。该应用的主要目的是了解胃肠道（GI）DC的作用和病毒在食物过敏的发展中所起的作用，这是基于肺部先前的发现，在肺中，呼吸道病毒启动了DC依赖性途径，最终导致特应疾病的发展。在肺中，病毒感染诱导了DC上IgE（FCERI）的高亲和力受体的表达。该受体的交联导致Th2细胞的趋化剂释放。病毒感染期间暴露于非病毒抗原对非病毒抗原的IgE。因此，这些数据支持以下假设：IgE介导的FCER在直流电上的交联导致募集和分化的Th2细胞启动IgE产生针对无害的环境抗原。如果该机制在胃肠道中起作用，它将解释IgE对食物过敏原的产生和食物过敏的发展。我们发现，GI病毒感染以类似于我们在肺中看到的方式诱导GI DC上的FCERI。因此，为了检验胃肠道病毒感染引发DC依赖性途径的假设最终导致食品过敏的发展，我们提出了以下两个具体目的：AIM I.定义GI树突状细胞FCERI交叉链接对树枝状细胞功能的影响。在此目标中，将利用在体外方法探索GI DC上的交联FCERI是否会导致Th2趋化剂释放，并将T细胞偏向Th2表型。目标II。表征GI树突状细胞FCERI表达与IgE之间的联系。在这种目标中，将利用体内方法来探索GI DC FCERI在Th2细胞募集和发育中的作用，以及在GI病毒感染期间对食物过敏原的IgE产生。这些研究的相关性是它们提供了有关食物过敏发展的机制的重要知识。此外，这些研究为动物模型提供了基础，在该模型中，可以开发新疗法以治疗或防止食物过敏。