Kupffer Cells in Liver Immunopathology

描述（由申请人提供）：肝脏的独特之处在于它能捕获并杀死活化的CD8+ T细胞。这就导致了肝炎的发生，它不是由CD8+ T细胞直接识别肝细胞上的抗原驱动的，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（KCs）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，肝炎可能是病毒感染过程中产生的大量CD8+ T细胞被肝脏清除的一般结果。其次，我们对旁观者肝炎的分析揭示了KCs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。我们最近开发了一种肝营养病毒感染模型，使用一种腺相关病毒（AAV）编码SIINFEKL抗原，由来自OT-1转基因小鼠的CD8+ T细胞识别。利用AAV-OVA和流感模型，我们提出了实验来验证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的假设（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）杀伤抑制抗病毒CTL反应（Aim 2）， kc介导的旁观者效应即使在肝内感染的情况下也会导致肝损伤（Aim 3）。最后，我们提出在肝营养病毒感染的AAV- OVA模型中测试选择性抑制KC活性作为提高病毒清除和减少肝损伤的新疗法。这些实验将揭示KCs如何影响肝脏中ctl依赖的免疫反应，并可能阐明HCV等肝营养病原体逃避免疫清除并建立慢性感染的机制。

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.