Kupffer Cells in Liver Immunopathology

描述(申请人提供)：肝脏是独一无二的，因为它捕获并杀死激活的CD8+T细胞。这导致了肝炎的发展，而不是由CD8+T细胞对肝细胞表面抗原的直接识别推动的，而是由间接或旁观者机制推动的。我们使用一种呼吸道病毒(甲型流感)在肝脏中驱动抗原特异性CD8+T细胞的扩张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。这项工作的意义有两个：首先，我们表明，旁观者肝炎发生在感染流感的患者和小鼠身上，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。其次，我们对旁观者肝炎的分析揭示了KCs在介导肝内CD8+T细胞的缺失以及诱导相关的肝损伤中的重要性。我们最近利用一种腺相关病毒(AAV)建立了一种肝营养性病毒感染的模型，该病毒编码由来自OT-1转基因小鼠的CD8+T细胞识别的SIINFEKL抗原。利用这个AAV-OVA和一个流感模型，我们提出了实验来检验KC激活(通过干扰素-g和TNFa)对于CD8+T细胞的删除和肝炎的产生(目标1)都是关键的假设。此外，我们假设KC介导的抗病毒细胞毒性T淋巴细胞(CTL)杀伤抑制了抗病毒CTL反应(目标2)，并且即使在肝内感染的情况下，KC介导的旁观者效应也会导致肝损伤(目标3)。最后，我们建议在我们的AAV-OVA肝营养性病毒感染模型中，测试选择性抑制KC活性作为一种新的治疗方法来改善病毒清除和减少肝脏损伤。这些实验将阐明KCs如何影响肝脏中依赖CTL的免疫反应，并可能阐明丙型肝炎病毒等肝营养性病原体逃避免疫清除和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.