Different procarcinogenic potentials of lymphocyte subsets in a transgenic mouse model of chronic hepatitis B
Different procarcinogenic potentials of lymphocyte subsets in a transgenic mouse model of chronic hepatitis B
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DOI：
10.1158/0008-5472.can-03-3817
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发表时间：
2004-05-01
期刊：
影响因子：
11.2
通讯作者：
Kaneko, S
中科院分区：
文献类型：
--
作者：
Nakamoto, Y;Suda, T;Kaneko, S
对肝炎病毒的免疫应答被认为参与慢性肝炎的发展;然而，其致病潜力尚未明确定义。目前的研究，使用慢性B型肝炎的转基因小鼠模型，旨在确定免疫细胞亚群对诱导肝细胞癌发生的肝病进展的相对贡献。用从B型肝炎表面抗原致敏的同基因非转基因供体获得的CD 4（+）和CD 8（+）T细胞富集或去除以及B细胞去除的脾细胞过继转移B型肝炎病毒转基因小鼠。由此产生的肝脏疾病，肝细胞凋亡，再生和肿瘤的发展进行了评估，并与接受普通脾细胞的小鼠的表现进行了比较。转移富含CD 8（+）的脾细胞导致疾病动力学延长，肝细胞凋亡和再生程度显著增加。在14只小鼠中的12只中，转移导致多发性肝细胞癌（HCC），与转移总脾细胞的小鼠中观察到的表现相当。相比之下，接受了富含CD 4（+）细胞的小鼠表现出较低的肝脏疾病水平和较少的HCC发病率（4/17）。该实验还显示，所有患有HCC的小鼠组都产生了可比较的平均肿瘤数量和大小。在该模型中，B细胞耗竭对疾病动力学没有影响。综上所述，这些结果表明，由CD 8（+）T细胞亚群诱导的致病事件是导致慢性肝病增加肿瘤发病率的主要原因，表明它们在触发肝癌发生过程中的潜力。
The immune response to hepatitis viruses is believed to be involved in the development of chronic hepatitis; however, its pathogenetic potential has not been clearly defined. The current study, using a transgenic mouse model of chronic hepatitis B, was designed to determine the relative contributions of the immune cell subsets to the progression of liver disease that induces hepatocellular carcinogenesis. Hepatitis B virus transgenic mice were adoptively transferred with CD4(+) and CD8(+) T cell-enriched or -depleted and B cell-depleted splenocytes obtained from hepatitis B surface antigen-primed, syngeneic nontransgenic donors. The resultant liver disease, hepatocyte apoptosis, regeneration, and tumor development were assessed and compared with the manifestations in mice that had received unfractionated spleen cells. Transfer of CD8(+)-enriched splenocytes caused prolonged disease kinetics, and a marked increase in the extent of hepatocyte apoptosis and regeneration. In 12 of 14 mice the transfer resulted in multiple hepatocellular carcinomas (HCCs) comparable with the manifestations seen in the mice transferred with total splenocytes. in contrast, mice that had received CD4(+)-enriched cells demonstrated lower levels of liver disease and developed fewer incidences of HCC (4 of 17). The experiment also revealed that all of the groups of mice complicated with HCC developed comparable mean numbers and sizes of tumors. B-cell depletion had no effect on disease kinetics in this model. Taken together, these results demonstrate that the pathogenetic events induced by CD8(+) T-cell subset are primarily responsible for the induction of chronic liver disease that increases tumor incidence, suggesting their potential in triggering the process of hepatocarcinogenesis.