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局部应用CpG寡聚脱氧核苷酸联合OX40单抗治疗肝细胞癌小鼠模型的效果分析
Clinical effect of topical application of CpG oligodeoxynucleotide combined with OX40 monoclonal antibody for mouse model of hepatocellular carcinoma
文章发布日期:2019年08月19日  来源:  作者:马士朝,张超群,孙殿兴  点击次数:87次  下载次数:11次

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【摘要】:目的探讨局部应用CpG寡聚脱氧核苷酸(CpG-ODN)联合OX40单抗方案对肝细胞癌的疗效,以及对远处同源肿瘤的治疗效果。方法在BALB/c雄性小鼠四肢腋窝皮下注射H22单细胞悬液,建立荷瘤模型,7 d后筛选出30只荷瘤体积相当的小鼠,随机分成模型对照组、CpG组、CpG+OX40组,每组10只,并在左下肢瘤内注射药物。选取10只同批正常小鼠作为正常对照组。计算荷瘤体积,ELISA法检测血清IL-12和IFNγ浓度,流式细胞术检测脾脏CD8+T淋巴细胞比例,比较3组小鼠治疗后的生存情况。计量资料多组间比较采用重复测量设计资料的方差分析和单因素方差分析,进一步两两组间比较采用LSD-t检验;采用log-rank检验分析3组小鼠(不包含正常组)生存率,并绘制生存曲线。结果给予治疗后,模型对照组荷瘤呈进行性增长,血清IL-12和IFNγ水平、脾脏CD8+T淋巴细胞比例较正常对照组均减低(P值均<0.05)。与模型对照组相比,CpG组和CpG+OX40组干预荷瘤体积均缩小(P值均<0.05);CpG+OX40组远处荷瘤体积比CpG组和模型对照组增长减慢(P值均<0.05),但CpG组远处荷瘤体积与模型对照组差异无统计学意义(P>0.05)。与模型对照组相比,两实验组血清中IL-12和IFNγ水平及脾脏CD8+T淋巴细胞比例均升高(P值均<005),且CpG+OX40组高于CpG组(P值均<0.05)。CpG+OX40组小鼠生存率均高于模型对照组和CpG组(P值均<0.05),CpG组与模型对照组之间差异无统计学意义(P>0.05)。结论OX40单抗联合CpG-ODN可使治疗处肝脏肿瘤缩小,并有效减缓远处肿瘤增长,延长小鼠生存时间。
【Abstract】:ObjectiveTo investigate the clinical effect of topical application of CpG-ODN combined with OX40 monoclonal antibody in the treatment of hepatocellular carcinoma and its therapeutic effect on distant homologous tumors. MethodsH22 single cell suspension was subcutaneously injected into the axilla of the four limbs of BALB/c male mice to establish a tumor-bearing model. After seven days, 30 mice with a similar tumor volume were screened out and randomly divided into model control group, CpG group, and CpG+OX40 group, with 10 mice in each group, and drugs were injected into the tumor in the left lower limb. Ten normal mice in the same batch were selected as normal control group. Tumor volume was calculated, ELISA was used to measure the serum levels of interleukin-12 (IL-12) and interferon-γ (IFNγ), and flow cytometry was used to measure the percentage of CD8+ T lymphocytes in the spleen. The three groups were compared in terms of survival after treatment. Repeated measures analysis of variance and one-way analysis of variance were used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. The log-rank test was used to analyze survival rate for the model control group, CpG group, and CpG+OX40 group, and survival curves were plotted. ResultsAfter treatment, the model control group had progressive growth of tumor, with significantly lower serum levels of IL-12 and IFNγ and percentage of spleen CD8+ T lymphocytes than the normal control group (all P<0.05). Compared with the model control group, the CpG group and the CpG+OX40 group had a significant reduction in tumor volume after intervention (all P<0.05). The CpG+OX40 group had a significantly lower growth rate of distant tumor than the CpG group and the model control group (all P<0.05), but there was no significant difference in distant tumor volume between the CpG group and the model control group (P>0.05). Compared with the model control group, the CpG group and the CpG+OX40 group had significant increases in serum levels of IL-12 and IFN-γ and percentage of spleen CD8+ T lymphocytes (all P<0.05), which were significantly higher in the CpG+OX40 group than in the CpG group (all P<0.05). The CpG+OX40 group had a significantly higher survival rate than the model control group and the CpG group (both P<005), while there was no significant difference between the CpG group and the model control group (P>0.05). ConclusionOX40 monoclonal antibody combined with CpG-ODN can reduce liver tumor volume, effectively slow down the growth of distant tumors, and prolong the survival time of mice.
【关键字】:癌, 肝细胞; OX40; CpG寡聚脱氧核苷酸; 免疫疗法; 小鼠, 近交BALB C; 动物实验
【Key words】:carcinoma, hepatocellular; OX40; CpG oligodeoxynucleotide; immunotherapy; mice, inbred BALB C; animal experimentation
【引证本文】:MA SZ, ZHANG CQ, SUN DX. Clinical effect of topical application of CpG oligodeoxynucleotide combined with OX40 monoclonal antibody for mouse model of hepatocellular carcinoma[J]. J Clin Hepatol, 2019, 35(9): 1985-1989. (in Chinese)
马士朝, 张超群, 孙殿兴. 局部应用CpG寡聚脱氧核苷酸联合OX40单抗治疗肝细胞癌小鼠模型的效果分析[J]. 临床肝胆病杂志, 2019, 35(9): 1985-1989.

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