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。

基本信息

批准号：
9340984
负责人：
Hannah Leigh Miller
金额：
$ 3.07万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/9340984
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 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 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 Mucositis 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 Staining method Stains Staphylococcal Enterotoxin B Structure of aggregated lymphoid follicle of small intestine Symptoms T-Cell Proliferation T-Lymphocyte Th2 Cells Therapeutic Therapeutic Intervention Time Tissues Transgenic Mice Transplantation Viral Virus Diseases allergic response anergy 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

项目摘要

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.

项目摘要该研究建议的目的是检查浆细胞类动物树突状细胞（PDC）在胃肠道系统中的免疫耐受性产生。病毒感染期间PDC的生物学对已经进行了充分的研究，很明显，这些细胞具有促进快速和促进的细胞机制响应病毒核酸的促炎性I型干扰素的强大产生。但是，在模型中癌症，移植和过敏，PDC可以诱导耐受性并抑制免疫反应。此外，先前的研究表明，肠道相关的PDC可能抑制炎症的产生对通过饮食提供的抗原的反应。为了进一步阐明这些细胞的耐受功能，我们建议研究PDC如何影响食物过敏模型。使用BDCA2-DTR转基因小鼠可以在很长一段时间内特异性地耗尽PDC，我们将1）检查PDC如何影响 CD4 T细胞在稳定状态期间对饮食抗原的反应以及通过佐剂的共同给药，2）评估PDC在A的致敏和效应阶段的作用食物过敏和过敏反应的临床前模型。从我们以前的研究中的过敏性接触模型中超敏反应，我们发现PDC耗竭通过改变先天和免疫反应对过敏原的自适应阶段。因此，我们假设PDC将限制病理在食物过敏模型中，通过影响对过敏原的粘膜免疫反应和/或抑制粘膜免疫反应效应子Th2细胞的分化。拟议的研究将更好地了解胃肠道过敏的发病机理，可能会改善预防或治疗选择受这种疾病影响的人口不断增长。