Imaging T Cell Airway Responses during Inflammation

炎症期间 T 细胞气道反应的成像

基本信息

批准号：
8239549
负责人：
MATTHEW F KRUMMEL
金额：
$ 32.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8239549
关键词：
Abbreviations Acute Address Affect Allergens Allergic Alveolar Alveolar Macrophages Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Asthma Attenuated B-Lymphocytes Bacteria Blood Circulation Breathing Bronchi Bronchoalveolar Lavage Bronchus-Associated Lymphoid Tissue CD27 Antigens Cell Communication Cell surface Cells Chronic Dendrites Dendritic Cells Discrimination Disease DsRed Environment Epithelial Eragrostis Feedback Frequencies Goals Green Fluorescent Proteins Guanine Nucleotide Dissociation Inhibitors Hen Egg Lysozyme ITGAX gene IgE Image Imaging Device Immune Immune response Immune system In Vitro Infection Inflammation Inflammatory Inflammatory Response Interleukin-4 Kinetics Label Lead Life Lung Lymphatic Lymphoid Tissue Macrophage Colony-Stimulating Factor Mediastinal Mediating Modeling Mus Mycoplasma Mycoplasma Infections Mycoplasma pulmonis Nature Organ Outcome Ovalbumin Particle Size Particulate Pattern Phagocytosis Phenotype Population Production Reaction Regulation Regulatory T-Lymphocyte Relative (related person)Role Route Sampling Severities Site Structure of parenchyma of lung Surface Surveys Synapses T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Tissues Transgenes Transgenic Organisms Viral Viral Tumor Antigens airway hyperresponsiveness airway inflammation airway remodeling arginase c-fms Proto-Oncogenes cell motility cytokine immunogenic insight lymph nodes macrophage mast cell mouse langerin mouse model novel particle promoter red fluorescent protein response trafficking uptake

项目摘要

The lung Is a unique epithelial surface at which inhaled particles, be they inert, bacteria or viral, are trapped in very close proximity to the bloodstream and in a filigree of epithelial surfaces. This presents unique spatial challenges for the T cells of the immune system to properly survey these antigens. Like many epithelial tissues, a selection of Immune macrophage and dendritic cells are poised within and beneath the surface to engulf and either neutralize, or to induce a more profound response to the Insult. During inflammatory insults including those of allergic but also bacterial or viral insults, the lung microenvironment physically changes. This new Project 2 will use live-imaging of viable lung and airways to determine how antigens traffic Into the lung and subsequently activate T cells, focusing the majority of effort upon a mouse model of asthma. The primary Issue being addressed is how inflammatory environments create a feedback loop that promotes accelerated immune responses and thus an enhanced inflammatory environment. We hypothesize that inflammation in the lung airway and aveolae creates a hyperreactive milieu for T lymphocyte priming. This milieu in turn is highly facilltative for synaptic interactions and thus increased production of lung remodeling factors Including cytokines. We propose that there are three distinct components of this. First, that there is a shift in the numbers, localization, antigen uptake and trafficking features between tolerizing phagocytic macrophages and highly immunogenic dendritic cells. The features of inflammatory antigens as well as the features of a remodeled milieu are both proposed to be directly responsible for the shift in the nature of APC which interact with T cells. Second, a shift In local polyclonal and antigen-specific regulatory T cells,modulated in part by the changes in APC population, subsequently modulates the activation of T cells. Finally, that T cells and their APC are modulated by airway remodeling and inflammation induced by agents such as Mycoplasma pulmonis or mast cell depletion. Thus, inflammation creates a fertile stimulatory ground for responses to inhaled antigens.

肺是一个独特的上皮表面，吸入的颗粒，无论是惰性颗粒、细菌还是病毒，都被困在非常靠近血流的地方，并被困在上皮表面的细丝中。这对免疫系统 T 细胞正确调查这些抗原提出了独特的空间挑战。与许多上皮组织一样，选择的免疫巨噬细胞和树突细胞在表面内部和表面下方准备吞噬并中和或诱导对侮辱的更深刻的反应。在炎症损伤期间，包括过敏性损伤以及细菌或病毒损伤，肺部微环境会发生物理变化。这个新项目 2 将使用活肺和气道的实时成像来确定抗原如何进入肺部并随后激活 T 细胞，并将大部分精力集中在小鼠哮喘模型上。正在解决的主要问题是炎症环境如何创建一个反馈循环，促进加速免疫反应，从而增强炎症环境。我们假设肺气道和肺泡中的炎症为 T 细胞创造了一个过度反应的环境淋巴细胞启动。这种环境反过来非常有利于突触相互作用，从而增加肺重塑因子（包括细胞因子）的产生。我们建议其中包含三个不同的组成部分。首先，耐受吞噬巨噬细胞和高免疫原性树突细胞之间的数量、定位、抗原摄取和运输特征发生了变化。炎症抗原的特征以及重塑环境的特征都被认为是直接影响的。负责与 T 细胞相互作用的 APC 性质的转变。其次，局部多克隆和抗原特异性调节 T 细胞的转变，部分受到 APC 群体变化的调节，随后调节 T 细胞的激活。最后，T 细胞及其 APC 受到气道重塑和肺支原体或肥大细胞耗竭等物质诱导的炎症的调节。因此，炎症为对吸入抗原的反应创造了肥沃的刺激基础。