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：
7251487
负责人：
Ian NICHOLAS Crispe
金额：
$ 37.87万
依托单位：
UNIVERSITY OF ROCHESTER
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7251487
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 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 Numbers OVA-8 Outcome Ovalbumin Pathway interactions Patients Peptide Fragments Peptide Nucleic Acids Polymerase Chain Reaction 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 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）：肝脏的独特之处在于它捕获并杀死活化的 CD8+ T 细胞。这导致肝炎的发展，这不是由CD8+ T细胞对肝细胞上抗原的直接识别驱动的，而是由间接或旁观者机制驱动的。我们使用呼吸道病毒（甲型流感）驱动肝脏中抗原特异性 CD8+ T 细胞的扩增和积累的初步研究表明，这种旁观者肝炎需要库普弗细胞 (KC) 的存在。这项工作的意义是双重的：首先，我们表明旁观者肝炎发生在感染流感的患者和小鼠中，并且肝炎可能是病毒感染过程中产生的大量 CD8+ T 细胞被肝脏清除的普遍结果。感染。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中的重要性。我们最近使用编码 SIINFEKL 抗原的腺相关病毒 (AAV) 开发了一种肝营养病毒感染模型，该抗原可被 OT-1 转基因小鼠的 CD8+ T 细胞识别。使用该 AAV-OVA 和流感模型，我们提出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（目标 1）。此外，我们假设 KC 介导的抗病毒细胞毒性 T 淋巴细胞 (CTL) 杀伤抑制抗病毒 CTL 反应（目标 2），并且 KC 介导的旁观者效应甚至在肝内感染的情况下也会导致肝损伤（目标 3））。最后，我们建议测试选择性抑制 KC 活性作为一种新疗法，以在我们的 AAV-OVA 保肝病毒感染模型中提高病毒清除率并减少肝损伤。这些实验将揭示 KC 如何影响肝脏中 CTL 依赖性免疫反应，并可能阐明 HCV 等保肝病原体逃避免疫清除并建立慢性感染的机制。