肝癌NK细胞免疫抑制机制的研究
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摘要
[目的]:建立人肝癌裸鼠皮下-肝原位移植瘤模型及NK细胞分离方法;检测NK细胞的细胞毒活性及其活化性受体NKG2D的表达;观察肝脏和脾脏组织病理变化。
[方法]:①建立人肝癌裸鼠皮下-肝原位移植瘤模型先用人肝癌细胞株Hep3B接种于裸鼠皮下,形成皮下移植瘤,然后用此移植瘤组织再接种于裸鼠肝内,建立肝原位移植瘤模型(间接肝原位移植瘤模型);②检测裸鼠原发性肝癌对NK细胞免疫活性的影响分别用Ficoll-Hypaque分层液、酶消化法和机械法初步制备裸鼠外周血、肝脏及脾脏混合淋巴细胞悬液后,用Percoll不连续密度梯度分离法分离NK细胞;用LDH方法检测NK细胞的细胞毒活性;用流式细胞技术检测不同组织NK细胞NKG2D表达百分率;用H-E染色观察肝脏移植瘤对肝脏和脾脏淋巴细胞的影响。
[结果]:①建立的间接肝原位移植瘤模型能稳定传代,移植瘤存活率达100%;②Percoll不连续密度梯度分离法分离的NK细胞纯度可达到68.5%;③外周血、肝脏及脾脏的NK细胞毒活性及NKG2D受体表达随着肿瘤生长逐渐下降,其中肝脏NK细胞毒活性及NKG2D表达下降明显;④荷瘤裸鼠肝脏癌组织与皮下瘤相同,癌组织异型性与时间呈正相关,脾脏淋巴小结在第4周增生明显,第8周小梁结构增多。
[结论]:①人肝癌裸鼠皮下-肝原位移植瘤模型具有高存活率的优点,它的建立为人类肝癌的研究提供了理想的工具;②成功建立了裸鼠NK细胞分离方法;③原发性肝癌通过下调NKG2D的表达,对NK细胞有免疫抑制作用,这种作用主要发生在肝脏,但对外周血和脾脏也有影响。
【Objective】:To establish the orthotopic transplantation tumor model from the subcutaneous model of human hepatocellular carcinomas (HCC) in nude mice and the techniques of isolation hepatic NK cells. Then to investigate the cytotoxicity of NK cells and the expression of active NKG2D receptor. Eventually, to observe the pathological changes of liver and spleen.
【Methods】:ⅠEstablishment of the orthotopic transplantation tumor model from the subcutaneous model of human hepatocellular carcinoma in nude mice: Hep3B cells were subcutaneously transplanted to form subcutaneous transplantation tumors in nude mice . Then the subcutaneous transplantation tumors were injected into liver to form the orthotopic transplantation tumor model (indirect orthotopic model) in nude mice.ⅡThe effects of the primary hepatocellular carcinoma on the immune activity of NK cells in nude mice: Total lymphocytes from the blood , liver and spleen of the nude mice were prepared by using Ficoll-Hypaque, digestive enzymes and mechanical dissection , respectively. Then NK cells were purified by Percoll discontinuous density gradient centrifugation , and the cytotoxicity of NK cells was detected by LDH method . Moreover, the NKG2D receptor expression of NK cells was measured by flow cytometry. Subsequently, the effects of the hepatic transplantation tumor on the lymphocytes of liver and spleen were analyzed by H-E staining.
【Results】:ⅠThe indirect orthotopic model can stably be propagated. The survival rates of the transplantation tumor were about 100%.ⅡThe purity of NK cells separated by Percoll discontinuous density gradient centrifugation reached to 68.5%.ⅢThe decrease of the cytotoxicity of NK cells and NKG2D receptor expression in peripheral blood, liver and spleen was associated with the growth of hepatocellular carcinoma , and this tendency was significantly in the liver.ⅣBoth the subcutaneous and hepatic transplantation tumor was homology. The heteromorphism of hepatocellular carcinoma was positive correlated with the growth time of tumors. The hyperplasia lymph follicle obviously increased in the spleen after 4 weeks, and the spleen trabecula significantly increased after 8 weeks.
【Conclusion】:ⅠThis model is an ideal means for study of HCC.ⅡNK cells are successfully purified.ⅢThe primary hepatocellular carcinoma has the immunosuppression effects upon NK cells though down-regulating the expression of NKG2D. Such effects are obvious in liver ,comparing with peripheral blood or spleen.
[方法]:①建立人肝癌裸鼠皮下-肝原位移植瘤模型先用人肝癌细胞株Hep3B接种于裸鼠皮下,形成皮下移植瘤,然后用此移植瘤组织再接种于裸鼠肝内,建立肝原位移植瘤模型(间接肝原位移植瘤模型);②检测裸鼠原发性肝癌对NK细胞免疫活性的影响分别用Ficoll-Hypaque分层液、酶消化法和机械法初步制备裸鼠外周血、肝脏及脾脏混合淋巴细胞悬液后,用Percoll不连续密度梯度分离法分离NK细胞;用LDH方法检测NK细胞的细胞毒活性;用流式细胞技术检测不同组织NK细胞NKG2D表达百分率;用H-E染色观察肝脏移植瘤对肝脏和脾脏淋巴细胞的影响。
[结果]:①建立的间接肝原位移植瘤模型能稳定传代,移植瘤存活率达100%;②Percoll不连续密度梯度分离法分离的NK细胞纯度可达到68.5%;③外周血、肝脏及脾脏的NK细胞毒活性及NKG2D受体表达随着肿瘤生长逐渐下降,其中肝脏NK细胞毒活性及NKG2D表达下降明显;④荷瘤裸鼠肝脏癌组织与皮下瘤相同,癌组织异型性与时间呈正相关,脾脏淋巴小结在第4周增生明显,第8周小梁结构增多。
[结论]:①人肝癌裸鼠皮下-肝原位移植瘤模型具有高存活率的优点,它的建立为人类肝癌的研究提供了理想的工具;②成功建立了裸鼠NK细胞分离方法;③原发性肝癌通过下调NKG2D的表达,对NK细胞有免疫抑制作用,这种作用主要发生在肝脏,但对外周血和脾脏也有影响。
【Objective】:To establish the orthotopic transplantation tumor model from the subcutaneous model of human hepatocellular carcinomas (HCC) in nude mice and the techniques of isolation hepatic NK cells. Then to investigate the cytotoxicity of NK cells and the expression of active NKG2D receptor. Eventually, to observe the pathological changes of liver and spleen.
【Methods】:ⅠEstablishment of the orthotopic transplantation tumor model from the subcutaneous model of human hepatocellular carcinoma in nude mice: Hep3B cells were subcutaneously transplanted to form subcutaneous transplantation tumors in nude mice . Then the subcutaneous transplantation tumors were injected into liver to form the orthotopic transplantation tumor model (indirect orthotopic model) in nude mice.ⅡThe effects of the primary hepatocellular carcinoma on the immune activity of NK cells in nude mice: Total lymphocytes from the blood , liver and spleen of the nude mice were prepared by using Ficoll-Hypaque, digestive enzymes and mechanical dissection , respectively. Then NK cells were purified by Percoll discontinuous density gradient centrifugation , and the cytotoxicity of NK cells was detected by LDH method . Moreover, the NKG2D receptor expression of NK cells was measured by flow cytometry. Subsequently, the effects of the hepatic transplantation tumor on the lymphocytes of liver and spleen were analyzed by H-E staining.
【Results】:ⅠThe indirect orthotopic model can stably be propagated. The survival rates of the transplantation tumor were about 100%.ⅡThe purity of NK cells separated by Percoll discontinuous density gradient centrifugation reached to 68.5%.ⅢThe decrease of the cytotoxicity of NK cells and NKG2D receptor expression in peripheral blood, liver and spleen was associated with the growth of hepatocellular carcinoma , and this tendency was significantly in the liver.ⅣBoth the subcutaneous and hepatic transplantation tumor was homology. The heteromorphism of hepatocellular carcinoma was positive correlated with the growth time of tumors. The hyperplasia lymph follicle obviously increased in the spleen after 4 weeks, and the spleen trabecula significantly increased after 8 weeks.
【Conclusion】:ⅠThis model is an ideal means for study of HCC.ⅡNK cells are successfully purified.ⅢThe primary hepatocellular carcinoma has the immunosuppression effects upon NK cells though down-regulating the expression of NKG2D. Such effects are obvious in liver ,comparing with peripheral blood or spleen.
引文
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