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

• 批准号: 7638423
• 负责人: Sun-Sang Joseph Sung
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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/7638423
• 关键词: Adoptive Transfer; Affect; All-Trans-Retinol; Allergens; Allergic; Allergic Reaction; Allergy to peanuts; Anatomy; Animal Model; Antibodies; Antigens; 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; 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; Weaning; Wild Type Mouse; cell type; chemokine; eosinophil; food allergen; in vivo; lymph nodes; macrophage-derived chemokine; mutant; novel; research study; response; secretory protein

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（申请人提供）：食物过敏影响3-6%的人口，并且难以诊断和治疗。对食物抗原的过敏反应通常通过粘膜耐受来抑制。维持这种食物耐受性的一个关键因素是调节性T细胞，而调节性T细胞又可以由表达粘附分子CD 103的树突状细胞亚群诱导。这种树突状细胞类型提供了食物过敏原和调节性T细胞与耐受性之间的联系，因为它们位于胃肠道的上皮层，并配备有紧密连接蛋白，便于进入肠腔。然而，CD 103 + DC也可以激活参与过敏反应的辅助性T细胞2，并为IgE合成和嗜酸性粒细胞发育提供帮助。由于这种CD 103+树突状细胞类型在决定对食物过敏原的免疫应答是致耐受性的还是致过敏性的中占据如此重要的位置，因此有必要更彻底地了解这种树突状细胞类型在肠内过敏原应答中的功能。已经收集了大量的初步数据，显示该树突状细胞亚群与其他树突状细胞亚群之间的表型和功能差异，并且已经产生了用于研究食物过敏中的CD 103+树突状细胞的试剂和突变小鼠。本项目的长期目标是阐明CD 103+树突状细胞在肠道介导抗原反应中的功能，并开发用于食物过敏治疗的治疗剂。已经开发了用于诱导对卵清蛋白的肠过敏反应的动物模型，其中嗜酸性粒细胞增多、血清IgE水平、辅助性T细胞2应答、肠道炎症和腹泻作为过敏诱导的指标。还建立了调节性T细胞缺陷模型以及提供大量抗原特异性调节性T细胞的小鼠。这些小鼠将用于研究整合素CD 103和CD 103 + 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。具体目标是：（1）利用CD 103缺陷小鼠和抗CD 103抗体研究CD 103和CD 103+树突状细胞在介导卵白蛋白致敏反应中的作用。CD 103 + DC在过敏反应中的作用将通过用CD 103+野生型树突状细胞过继转移免疫CD 103缺陷型受体来证实;（2）研究不同剂量的卵清蛋白特异性调节性T细胞对调节性T细胞缺陷型卵清蛋白特异性T细胞受体转基因小鼠的反应的抑制。将研究抗原特异性调节性T细胞交叉抑制不相关抗原的应答的能力和通过CD 103+树突细胞合成趋化因子CCL 22/MDC的调节性T细胞刺激的能力。这些研究将确定CD 103+树突状细胞在食物过敏中的重要性，并可能有助于开发抗CD 103、调节性T细胞或CCL 22/MDC作为免疫治疗剂。