Parenchymal expression of CD86/B7.2 contributes to hepatitis C virus-related liver injury
Parenchymal expression of CD86/B7.2 contributes to hepatitis C virus-related liver injury
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DOI：
10.1128/jvi.79.16.10730-10739.2005
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发表时间：
2005-08-01
影响因子：
5.4
通讯作者：
Chan, TS
中科院分区：
文献类型：
--
作者：
Sun, JR;Tumurbaatar, B;Chan, TS
丙型肝炎病毒(HCV)感染是一个重大的全球健康问题。已知免疫共刺激信号分子(如B7)在肝脏的表达与丙型肝炎患者持续的肝损伤有关。然而，由于普遍缺乏病毒培养系统和足够的动物模型，这些分子在疾病发病机制中的作用尚不清楚。为了研究CD86在丙型肝炎病毒相关性肝损伤中的作用，我们建立了两个转基因小鼠系，它们可诱导表达丙型肝炎病毒结构蛋白，并在肝脏中结构性表达共刺激分子CD86/B7.2。使用基于流体力学的非病毒传递方案，我们在单转基因和双转基因小鼠的肝脏中诱导了丙型肝炎病毒转基因表达。我们发现，肝脏CD86的表达导致CD4(+)T细胞的激活和细胞因子(如白细胞介素2和干扰素)的产生增加，并且这些细胞的滞留与肝脏中更明显的坏死性炎症病变有关。综上所述，这些数据表明，肝细胞CD86表达增强的实质抗原递呈改变了CD4(+)T细胞的动态平衡和效应功能，并导致肝脏损伤。这项研究为探索基于免疫调节的治疗方法提供了额外的理由，这些治疗方法可以减少慢性丙型肝炎病毒感染者的疾病进展。
Hepatitis C virus (HCV) infection is a major global health problem. Hepatic expression of immune costimulatory signaling molecules (e.g., B7) is known to be associated with ongoing liver injury in hepatitis C patients. However, due to the general lack of viral culture systems and adequate animal models, the function of these molecules in disease pathogenesis is poorly understood. To investigate the role of CD86 in HCV-related liver injury, we developed two transgenic mouse lineages with inducible expression of HCV structural proteins and constitutive expression of the costimulatory molecule CD86/B7.2 in the liver. Using a hydrodynamic-based, nonviral delivery protocol, we induced HCV transgene expression in the livers of HCV and CD86 single- and double-transgenic mice. We found that hepatic CD86 expression resulted in increased activation of and cytokine production (e.g., interleukin-2 and gamma interferon) by CD4(+) T cells and that the retention of these cells was associated with more pronounced necroinflammatory lesions in the liver. Taken together, these data suggest that augmented, parenchymal antigen presentation conferred by hepatocyte CD86 expression alters homeostasis and effector functions of CD4(+) T cells and contributes to liver injury. This study provides an additional rationale for exploring immunomodulation-based therapies that could reduce disease progression in individuals with chronic HCV infection.