CD103+ Dendritic Cells and Regulatory T cells in Food Allergy

描述（由申请人提供）：食物过敏影响3-6%的人口，难以诊断和治疗。对食物抗原的过敏反应通常由黏膜耐受性控制。维持这种食物耐受性的关键角色是调节性T细胞，它反过来可以被表达粘附分子CD103的树突状细胞亚群诱导。这种树突状细胞类型在食物过敏原和调节性T细胞和耐受性之间提供了联系，因为它们位于胃肠道的上皮层，并配备了紧密连接蛋白，以便它们随时进入肠腔。然而，CD103+ DC也可以激活T辅助2细胞，参与过敏反应，并为IgE合成和嗜酸性粒细胞的发育提供帮助。由于这种CD103+树突状细胞类型在决定对食物过敏原的免疫反应是耐受性还是过敏性方面占据着如此重要的地位，因此更深入地了解这种树突状细胞类型在肠道过敏原反应中的功能是有必要的。大量的初步数据显示了CD103+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CD103+树突状细胞的试剂和突变小鼠。该项目的长期目标是阐明CD103+树突状细胞在肠道中介导抗原反应的功能，并开发治疗食物过敏的药物。建立了一种以嗜酸性粒细胞、血清IgE水平、辅助性T 2反应、肠道炎症和腹泻为过敏诱导指标的促卵白蛋白诱导肠道过敏反应的动物模型。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细胞的小鼠也已建立。这些小鼠将用于研究整合素CD103和CD103+ DC在食物过敏中的作用以及抗原特异性调节性T细胞抑制食物过敏的作用。具体目的是：(1)利用CD103缺陷小鼠和抗CD103抗体，研究CD103和CD103+树突状细胞在介导卵白蛋白过敏反应中的作用。CD103+ DC在过敏反应中的作用将通过免疫CD103缺陷受体，将CD103+野生型树突状细胞过继转移来证实；(2)研究分级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抑制作用。将研究抗原特异性调节性T细胞交叉抑制不相关抗原反应的能力，以及CD103+树突状细胞合成趋化因子CCL22/MDC对调节性T细胞的刺激。这些研究将确定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。

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.