Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages.
Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages.
复制标题
DOI：
10.1371/journal.ppat.1004032
复制
发表时间：
2014-03
期刊：
影响因子：
6.7
通讯作者：
Su L
中科院分区：
文献类型：
--
作者：
Bility MT;Cheng L;Zhang Z;Luan Y;Li F;Chi L;Zhang L;Tu Z;Gao Y;Fu Y;Niu J;Wang F;Su L
由于缺乏可靠的小动物模型，对慢性HBV感染和免疫发病机制了解甚少。在这里，我们报告了一个人源化的小鼠模型的发展与人类免疫系统和人类肝细胞重建免疫缺陷的A2/NSG（NOD.Cg-Prkdcscid Il 2 rgtm 1 Wjl/SzJ小鼠与人类HLA-A2转基因）与人类造血干细胞和肝祖细胞（A2/NSG-hu HSC/Hep小鼠）。A2/NSG-hu HSC/Hep小鼠支持HBV感染，约75%的HBV感染小鼠建立持续感染至少4个月。我们检测到人体免疫反应，尽管在肝脏受损，慢性肝脏炎症和肝纤维化的感染动物。HBV中和抗体在人源化小鼠中有效抑制HBV感染和相关肝病。此外，我们发现HBV介导的肝脏疾病与高水平的具有M2样活化表型的人巨噬细胞浸润相关。重要的是，在患有肝脏疾病的慢性乙型肝炎B患者中证实了类似的M2样巨噬细胞积聚。此外，基因表达分析表明，在急性HBV诱导的肝衰竭患者中，肝脏中M2样巨噬细胞的诱导与加速的肝纤维化和坏死相关。最后，我们证明，HBV促进M1和M2巨噬细胞在细胞培养研究中的M2样激活。我们的研究表明，A2/NSG-hu HSC/Hep小鼠模型在研究HBV感染、人体免疫应答和相关肝脏疾病方面具有重要价值。此外，这项研究的结果表明，巨噬细胞极化在B型肝炎病毒诱导的免疫损伤和肝脏病理中起着关键作用。全世界有超过3.5亿人慢性感染B型肝炎病毒（HBV），导致严重的肝脏疾病，包括纤维化和癌症。由于缺乏可靠的小动物模型，慢性HBV感染和疾病的机制知之甚少。在这里，我们报告了一种新的动物模型，可以有效地与人类免疫细胞和肝细胞重新填充。A2/NSG-hu HSC/Hep人源化小鼠模型支持持续的HBV感染、人免疫应答（尽管在肝脏中受损）、慢性肝脏炎症和肝纤维化。此外，我们发现HBV介导的肝脏免疫损伤和肝脏疾病与高水平的浸润的人免疫抑制/促纤维化巨噬细胞相关;这一结果在慢性HBV诱导的肝脏疾病患者和急性HBV诱导的肝衰竭患者中得到证实。重要的是，我们证明，HBV促进免疫抑制/促纤维化的巨噬细胞极化在人类巨噬细胞使用细胞培养模型。人源化小鼠模型是研究HBV感染、人体免疫应答和肝脏疾病的重要平台。此外，本研究的结果表明巨噬细胞活化在B型肝炎诱导的肝脏疾病中起关键作用，从而提供了一种新的治疗靶点。
The mechanisms of chronic HBV infection and immunopathogenesis are poorly understood due to a lack of a robust small animal model. Here we report the development of a humanized mouse model with both human immune system and human liver cells by reconstituting the immunodeficient A2/NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice with human HLA-A2 transgene) with human hematopoietic stem cells and liver progenitor cells (A2/NSG-hu HSC/Hep mice). The A2/NSG-hu HSC/Hep mouse supported HBV infection and approximately 75% of HBV infected mice established persistent infection for at least 4 months. We detected human immune responses, albeit impaired in the liver, chronic liver inflammation and liver fibrosis in infected animals. An HBV neutralizing antibody efficiently inhibited HBV infection and associated liver diseases in humanized mice. In addition, we found that the HBV mediated liver disease was associated with high level of infiltrated human macrophages with M2-like activation phenotype. Importantly, similar M2-like macrophage accumulation was confirmed in chronic hepatitis B patients with liver diseases. Furthermore, gene expression analysis showed that induction of M2-like macrophage in the liver is associated with accelerated liver fibrosis and necrosis in patients with acute HBV-induced liver failure. Lastly, we demonstrate that HBV promotes M2-like activation in both M1 and M2 macrophages in cell culture studies. Our study demonstrates that the A2/NSG-hu HSC/Hep mouse model is valuable in studying HBV infection, human immune responses and associated liver diseases. Furthermore, results from this study suggest a critical role for macrophage polarization in hepatitis B virus-induced immune impairment and liver pathology. Over 350 million people worldwide are chronically infected with the hepatitis B virus (HBV), which leads to severe liver diseases including fibrosis and cancer. The mechanisms of chronic HBV infection and disease are poorly understood due to a lack of a robust small animal model. Here we report a novel animal model that can be efficiently repopulated with both human immune and liver cells. The A2/NSG-hu HSC/Hep humanized mouse model supported persistent HBV infection, human immune responses, albeit impaired in the liver, chronic liver inflammation and liver fibrosis. In addition, we found that the HBV mediated liver immune impairment and liver disease was associated with high level of infiltrated human immuno-suppressive/pro-fibrogenic macrophages; this result was confirmed in chronic HBV-induced liver disease patients and acute HBV – induced liver failure patients. Importantly, we demonstrate that HBV promotes immuno-suppressive/pro-fibrogenic macrophage polarization in human macrophages using cell culture models. The humanized mouse model is a valuable platform in studying HBV infection, human immune response and liver diseases. Furthermore, results from this study suggest a critical role for macrophage activation in hepatitis B induced liver diseases, thus providing a novel therapeutic target.
登录
查看更多内容
影响因子：
46.9
作者：
Azuma, Hisaya;Paulk, Nicole;Grompe, Markus
通讯作者：
Grompe, Markus
影响因子：
13.5
作者：
Guidotti, JE;Mallet, VO;Gilgenkrantz, H
通讯作者：
Gilgenkrantz, H
影响因子：
4.3
作者：
Lin, Min;Chen, Qun;Chen, Mo-Rui
通讯作者：
Chen, Mo-Rui
影响因子：
13.5
作者：
KNODELL, RG;ISHAK, KG;WOLLMAN, J
通讯作者：
WOLLMAN, J
影响因子：
2.9
作者：
Choi, Jong Gi;Chung, Young-Hwa;Lee, Young Joo
通讯作者：
Lee, Young Joo