Elucidating the tolerogenic roles of plasmacytoid dendritic cells in the gastrointestinal system.

阐明浆细胞样树突状细胞在胃肠道系统中的耐受性作用。

• 批准号: 9762917
• 负责人: Hannah Leigh Miller
• 金额: $ 5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762917
• 关键词: Adjuvant; Affect; Allergens; Allergic; Allergic Disease; Anaphylaxis; Annexins; Antigen-Presenting Cells; Antigens; Apoptosis; Biological Assay; Biology; Body Temperature Changes; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Model; Cell physiology; Cells; Child; Clinical; Complex; Contact hypersensitivity; Cutaneous; Dendritic Cells; Development; Diet; Disease; Dose; Effector Cell; Exposure to; FOXP3 gene; Flow Cytometry; Fluorescein-5-isothiocyanate; Food Hypersensitivity; GATA3 gene; Gastrointestinal tract structure; Generations; Goals; Hand; Haptens; Histamine; Histology; Human; Hypersensitivity; IgE; Immune Tolerance; Immune response; Immune system; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Ingestion; Interferon Type I; Interferon Type II; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-4; Label; Lamina Propria; Lead; Mediating; Mediator of activation protein; Mesentery; Microscopy; Modeling; Mucosal Immune Responses; Mucosal Immune System; Mucositis; Mucous Membrane; Mus; Nucleic Acids; Oral; Pathogenesis; Pathology; Peripheral; Permeability; Phase; Population; Pre-Clinical Model; Production; Proteins; Reaction; Reporting; Research; Research Proposals; Role; Serum; Severities; Skin; Specific qualifier value; Stains; Staphylococcal Enterotoxin B; Structure of aggregated lymphoid follicle of small intestine; Symptoms; T cell response; T-Cell Proliferation; T-Lymphocyte; Th2 Cells; Therapeutic; Therapeutic Intervention; Time; Tissues; Transgenic Mice; Transplantation; Viral; Virus Diseases; allergic response; anergy; antigen-specific T cells; antiviral immunity; cytokine; feeding; food antigen; gastrointestinal; gastrointestinal system; improved; in vivo; insight; interest; intraepithelial; intraperitoneal; lymph nodes; mast cell; mucosal site; new therapeutic target; oral tolerance; patient population; physiologic model; response; theories; transcription factor

Project Summary The objective of this research proposal is to examine the role of plasmacytoid dendritic cells (pDC) in the generation of immune tolerance within the gastrointestinal system. The biology of pDC during viral infection has been well studied, and it is clear that these cells possess cellular machinery that facilitates rapid and robust production of proinflammatory type I interferons in response to viral nucleic acids. However, in models of cancer, transplant, and allergy, pDC can induce tolerance and inhibit an immune response. Furthermore, previous studies have suggested that gut associated pDC may suppress the generation of inflammatory responses to antigens delivered through the diet. To further elucidate the tolerogenic function of these cells, we propose to investigate how pDC impact a model of food allergy. Using the BDCA2-DTR transgenic mice which can be specifically depleted of pDC for extended periods of time, we will 1) examine how pDC influence the CD4 T cell response to dietary antigens during steady state and during abrogation of oral tolerance through coadministration of adjuvant, and 2) evaluate the role of pDC within the sensitization and effector phases of a preclinical model of food allergy and anaphylaxis. From our previous studies in a model of allergic contact hypersensitivity, we have discovered that pDC depletion exacerbates pathology by altering the innate and adaptive phases of the immune response to allergen. Thus, we hypothesize that pDC will limit pathology in a model of food allergy by influencing the mucosal immune response to allergen and/or by inhibiting the differentiation of effector Th2 cells. The proposed research will provide better insight into the pathogenesis of gastrointestinal allergy and may lead to improved preventative or therapeutic options for the growing population affected by this disease.

项目摘要 本研究的目的是检测浆细胞样树突状细胞（pDC）在肿瘤细胞中的作用。 在胃肠道系统内产生免疫耐受。病毒感染过程中pDC的生物学 已经得到了很好的研究，很明显，这些细胞具有细胞机制，促进快速和 响应病毒核酸的促炎I型干扰素的稳健产生。然而，在模型中 在癌症、移植和变态反应中，pDC可以诱导耐受性并抑制免疫应答。此外，委员会认为， 以前的研究表明，肠道相关的pDC可以抑制炎症的产生， 对通过饮食传递的抗原的反应。为了进一步阐明这些细胞的致耐受性功能， 我们建议研究pDC如何影响食物过敏模型。使用BDCA 2-DTR转基因小鼠 其可以在延长的时间段内特异性地耗尽pDC，我们将1）检查pDC如何影响 在稳定状态期间和口服耐受消除期间，CD 4 T细胞对饮食抗原的应答， 共施用佐剂，和2）评估pDC在免疫调节剂的致敏和效应阶段中的作用。 食物过敏和过敏反应的临床前模型。从我们之前的过敏性接触模型研究中 在超敏反应中，我们已经发现pDC耗竭通过改变先天性 对过敏原的免疫反应的适应性阶段。因此，我们假设pDC将限制病理学 在食物过敏模型中，通过影响对过敏原的粘膜免疫应答和/或通过抑制 Th 2效应细胞的分化。拟议的研究将提供更好的洞察力， 胃肠道过敏的发病机制，并可能导致改善预防或治疗选择， 越来越多的人受到这种疾病的影响。

项目成果

Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity.

皮肤引流淋巴结中树突状细胞亚群比例的改变会促进 Th2 驱动的接触性超敏反应。

• DOI: 10.1073/pnas.2021364118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Miller,HannahL;Andhey,PrabhakarSairam;Swiecki,MelissaK;Rosa,BruceA;Zaitsev,Konstantin;Villani,Alexandra-Chloe;Mitreva,Makedonka;Artyomov,MaximN;Gilfillan,Susan;Cella,Marina;Colonna,Marco
• 通讯作者: Colonna,Marco