CD103+ Dendritic Cells and Regulatory T cells in Food Allergy

食物过敏中的 CD103 树突状细胞和调节性 T 细胞

基本信息

批准号：
7539730
负责人：
Sun-Sang Joseph Sung
金额：
$ 22.73万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-18 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7539730
关键词：
Adam11 gene Adoptive Transfer Affect All-Trans-Retinol Allergens Allergic Allergic Reaction Allergy to peanuts Anatomy Animal Model Antibodies Antigens CCL22 gene CCR9 gene CD4 Positive T Lymphocytes CD8B1 gene Cell Adhesion Molecules Cell Communication Cell physiology Cells Colitis Complex Cytokine Receptors Data Dendritic Cells Development Diagnosis Diarrhea Disease Disease Outcome Disease susceptibility Dose Environmental Risk Factor Eosinophilia Epithelial Exhibits Food Food Hypersensitivity Gastrointestinal tract structure Gene Expression Profile Genetic Goals Hand Helper-Inducer T-Lymphocyte Homing Hypersensitivity ITGAM gene IgE Immunization Immunotherapeutic agent In Vitro Inbred BALB C Mice Individual Inflammation Inflammatory Inflammatory disease of the intestine Integrins Intestines Link Lung MHC Class I Genes Mediating Mesentery Microarray Analysis Modeling Mucous Membrane Mus Mutant Strains Mice Numbers Organ Ovalbumin Play Population Positioning Attribute Prevention Process Proteins Public Health Rag1 Mouse Reagent Role Route Serum Skin Sorting - Cell Movement Structure of aggregated lymphoid follicle of small intestine T-Cell Receptor T-Lymphocyte Th2 Cells Therapeutic Agents Tight Junctions Transgenes Transgenic Mice Visceral Vitamin A Weaning Wild Type Mouse cell type chemokine chlorambucil/dactinomycin/methotrexate protocol eosinophil food allergen in vivo lymph nodes macrophage-derived chemokine mutant novel research study response secretory protein

项目摘要

DESCRIPTION (provided by applicant): Food allergies affect 3-6% of the population and are difficult to diagnose and treat. Allergenic responses to food antigens are normally held in check by mucosal tolerance. A key player for maintaining this food tolerance is the regulatory T cells which in turn can be induced by a dendritic cell subset which expresses the adhesion molecule CD103. This dendritic cell type provides the link between food allergens and regulatory T cells and tolerance because they are located at the epithelial layer of the gastrointestinal tract and are equipped with tight junction proteins for their ready access to the intestinal lumen. However, CD103+ DC can also activate T helper 2 cells which participate in allergic responses and provide help for IgE synthesis and eosinophil development. Because this CD103+ dendritic cell type occupy such an important position in the decision of whether an immunological response to a food allergen is toleragenic or allergenic, more thorough understanding of the functions of this dendritic cell type in allergen responses in the intestines is warranted. Large amounts of preliminary data showing the phenotypic and functional differences between this and other dendritic cell subsets have been gathered and reagents and mutant mouse have been generated for the studies of CD103+ dendritic cells in food allergy. The long term goal of this project is to elucidate the function of CD103+ dendritic cells in mediating antigenic responses in the intestines and to develop therapeutic agents for food allergy treatment. An animal model for inducing intestinal allergic reactions to ovalbumin with eosinophilia, serum IgE levels, T helper 2 responses, intestinal inflammation, and diarrhea as indicators of allergy induction has been developed. A regulatory T cell deficient model as well as a mouse that provides large numbers of antigen-specific regulatory T cells have also been established. These mice will be used for studying the functions of integrin CD103 and CD103+ DC in food allergy and the efficacy of antigen-specific regulatory T cells in suppressing food allergies. The specific aims are: (1) to study the role of CD103 and CD103+ dendritic cells in mediating allergenic responses to ovalbumin using CD103 deficient mice and anti-CD103 antibodies. The role of CD103+ DC in allergic reactions will be confirmed by immunizing CD103 deficient recipients that are adoptive transferred with CD103+ wild-type dendritic cells; (2) to study the suppression of the responses of regulatory T cell deficient ovalbumin-specific T cell receptor transgenic mice by graded doses of ovalbumin-specific regulatory T cells. The ability of the antigen-specific regulatory T cell to cross-inhibit the responses of an unrelated antigen and the regulatory T cell stimulation by the synthesis of the chemokine CCL22/MDC by CD103+ dendritic cells will be studied. The studies will establish the importance of CD103+ dendritic cells in food allergy and may help in the development of anti-CD103, regulatory T cells, or CCL22/MDC as immunotherapeutic agents.

描述（由申请人提供）：食物过敏会影响3-6％的人口，难以诊断和治疗。通常，对食物抗原的过敏性反应通常会通过粘膜耐受性检查。维持这种食物耐受性的关键参与者是调节性T细胞，进而由表达粘附分子CD103的树突状细胞子集诱导。这种树突状细胞类型提供了食物过敏原与调节性T细胞和耐受性之间的联系，因为它们位于胃肠道的上皮层，并配备了紧密的连接蛋白，以便它们可以使用肠腔。但是，CD103+ DC还可以激活参与过敏反应的T辅助2个细胞，并为IgE合成和嗜酸性粒细胞发育提供帮助。因为这种CD103+树突状细胞类型在决定中对食物过敏原的免疫反应是否具有耐兴奋性或过敏性，因此对这种树突状细胞类型在肠道中的过敏原反应中的功能更详尽地理解。已经收集了大量的初步数据，显示了该和其他树突状细胞亚群之间的表型和功能差异，并为食物过敏中的CD103+树突状细胞的研究生成了试剂和突变小鼠。该项目的长期目标是阐明CD103+树突状细胞在介导肠中介导抗原反应并开发用于食物过敏治疗的治疗剂的功能。一种用于诱导肠胃蛋白与嗜酸性粒细胞，血清IgE水平，T助手2反应，肠炎和腹泻的动物模型，已开发出作为过敏诱导的指标。还建立了一个提供大量抗原特异性调节T细胞的调节性T细胞缺陷模型和小鼠。这些小鼠将用于研究整联蛋白CD103和CD103+ DC在食物过敏中的功能，以及抗原特异性调节性T细胞在抑制食物过敏中的功效。具体目的是：（1）研究CD103和CD103+树突状细胞在使用CD103缺陷小鼠和抗CD103抗体中介导对卵蛋白的过敏性反应中的作用。 CD103+ DC在过敏反应中的作用将通过免疫CD103的缺陷受体来证实，这些受体被用CD103+野生型树突状细胞转移。（2）研究调节性T细胞缺乏卵巢蛋白特异性T细胞受体转基因小鼠的抑制作用，分为椭圆蛋白特异性的调节性T细胞。将研究抗原特异性调节性T细胞通过CD103+树突状细胞合成通过趋化因子CCL22/MDC合成的无关抗原和调节性T细胞刺激的反应的能力。研究将确定CD103+树突状细胞在食物过敏中的重要性，并可能有助于抗CD103，调节性T细胞或CCL22/MDC作为免疫治疗剂的发展。