Kupffer Cells in Liver Immunopathology

肝脏免疫病理学中的库普弗细胞

基本信息

批准号：
7920895
负责人：
Ian NICHOLAS Crispe
金额：
$ 45.45万
依托单位：
SEATTLE BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7920895
关键词：
Ablation Acute Adoptive Transfer Affect Antibodies Antigen Targeting Antigens Antiviral Agents Apoptosis Apoptotic Applications Grants Back Bone Marrow Transplantation Bystander Effect CD8B1 gene Cell Death Cell Surface Receptors Cell-Mediated Cytolysis Cells Cessation of life Characteristics Chronic Chronic Active Hepatitis Cytotoxic T-Lymphocytes Dependence Dependovirus Development Dichloromethylene Diphosphonate Drug Delivery Systems Effectiveness Encapsulated Epitopes Event Generations Genotype Green Fluorescent Proteins Hepatic Hepatitis Hepatitis C virus Hepatitis C-Like Viruses Hepatocyte Immune response Immunity Immunofluorescence Immunologic Immunohistochemistry Impairment In Situ Nick-End Labeling Infection Inflammatory Response Influenza Injury Injury to Liver Interferons Kupffer Cells Lead Light Liposomes Liver Lymphocyte Function Macrophage Colony-Stimulating Factor Measures Mediating Modeling Molecular Mus Nature OVA-8 Outcome Ovalbumin Pathway interactions Patients Peptide Fragments Peptide Nucleic Acids Population Portal vein structure Principal Investigator Production Proteins RNA Interference Recombinant adeno-associated virus (rAAV)Recombinants Regulation Relative (related person)Research Personnel Role Satellite Viruses Signal Pathway Signal Transduction Site Staining method Stains T-Cell Receptor T-Lymphocyte Testing Therapeutic Time Transgenic Mice Transgenic Organisms Tumor Necrosis Factor Receptor Viral Viral hepatitis Virus Virus Diseases Work autocrine base cytotoxic design feeding immune clearance immunopathology improved influenzavirus inhibitor/antagonist intrahepatic killings liver allograft nanoparticle novel pathogen programs receptor research study respiratory virus response small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The liver is unique in that it traps and kills activated CD8+ T cells. This results in the development of hepatitis, which is not driven by the direct recognition of antigen on hepatocytes by CD8+ T cells, but by an indirect or bystander mechanism. Our preliminary studies using a respiratory virus (influenza A) to drive the expansion and accumulation of antigen-specific CD8+ T cells in the liver indicate that this bystander hepatitis requires the presence of Kupffer cells (KCs). The significance of this work is twofold: First, we show that bystander hepatitis occurs in patients as well as mice infected with influenza and that hepatitis may be a general consequence of the hepatic clearance of large numbers of CD8+ T cells generated during the course of virus infections. Secondly, our analysis of bystander hepatitis has revealed the importance of KCs in mediating the deletion of intrahepatic CD8+ T cells as well as inducing the associated liver damage. We have recently developed a model of hepatotrophic viral infection using an Adeno-Associated Virus (AAV) encoding the SIINFEKL antigen recognized by CD8+ T cells from the OT-1 transgenic mouse. Using this AAV-OVA and an influenza model, we propose experiments to test the hypothesis that KC activation (mediated through interferon-g and TNFa) is critical for both the deletion of CD8+ T cells and the generation of hepatitis (Aim 1). Furthermore, we postulate that KC-mediated killing of anti-viral cytotoxic T lymphocytes (CTLs) inhibits the antiviral CTL response (Aim 2) and that KC-mediated bystander effect contributes to liver damage even in the context of an intrahepatic infection (Aim 3). Finally, we propose to test selective inhibition of KC activity as a novel therapy to improve viral clearance and decrease liver damage in our AAV- OVA model of hepatotrophic virus infection. These experiments will shed light on how KCs affect CTL-dependent immune responses in the liver and may clarify the mechanism through which hepatotrophic pathogens such as HCV evade immune clearance and establish chronic infections.

描述（由申请人提供）：肝脏是独一无二的，因为它会捕获并杀死活化的CD8+ T细胞。这导致肝炎的发展，这不是由CD8+ T细胞在肝细胞上直接识别抗原的驱动，而是由间接或旁观者机制驱动的。我们使用呼吸道病毒（流感）的初步研究来推动肝脏中抗原特异性CD8+ T细胞的膨胀和积累，表明该旁观者肝炎需要kupffer细胞（KCS）。这项工作的重要性是双重的：首先，我们表明旁观者肝炎发生在患者以及感染流感的小鼠中，肝炎可能是病毒感染过程中大量CD8+ T细胞的肝清除率的总体结果。其次，我们对旁观者肝炎的分析揭示了KC在介导肝内CD8+ T细胞缺失以及诱导相关肝损伤方面的重要性。我们最近使用与OT-1转基因小鼠CD8+ T细胞识别的Siinfekl抗原相关病毒（AAV）开发了肝营养性病毒感染模型。使用这种AAV-OVA和一个流感模型，我们提出了实验来检验以下假设：KC激活（通过干扰素G和TNFA介导）对于CD8+ T细胞的缺失和肝炎的产生至关重要（AIM 1）至关重要（AIM 1）。此外，我们假设KC介导的抗病毒细胞毒性T淋巴细胞（CTL）抑制了抗病毒CTL反应（AIM 2），即使在肝内感染的背景下，AIM 3）也会有助于肝脏损害。最后，我们建议测试对KC活性的选择性抑制作用，作为一种新的疗法，以改善我们的肝营养性病毒感染模型中的病毒清除率并减少肝脏损伤。这些实验将阐明KC在肝脏中如何影响CTL依赖性免疫反应，并可以阐明肝营养性病原体（例如HCV逃避免疫清除率）的机制并建立慢性感染。