评价肿瘤疫苗免疫原性的新型人免疫系统小鼠模型
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国家自然科学基金资助项目(No.81573335,No.81673343,No.91753112)


A novel human immune system mice model for assessing the immunogenicity of cancer vaccines
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    摘要:

    人免疫系统(human immune system,HIS)小鼠大都用于评价肿瘤疫苗诱导细胞毒性T淋巴细胞(cytotoxic T lymphocyte,CTL)效应的能力,却不能准确反映肿瘤疫苗诱导体液免疫应答的能力。本研究利用密度梯度离心法分离人外周血单核细胞,与体外诱导分化的同源树突状细胞(dendritic cells,DCs)共移植到NCG小鼠中从而建立DC-HIS小鼠模型。在DC-HIS小鼠中,共移植的抗原递呈细胞(HLA-DR+CD11c+)能定植于模型小鼠脾脏;DCs共移植也显著提高了激活的人CD4+ T/CD8+ T细胞和人B细胞的比例,提示DCs-HIS小鼠能较好的模拟人体的免疫应答情况。利用所构建的DCs-HIS小鼠评价靶向HER2蛋白疫苗(NitraTh-HER2)的免疫原性,结果显示,NitraTh-HER2疫苗能够诱导HER2特异性人IgG抗体的产生,并具有显著的抗体依赖的细胞介导的细胞毒性作用(antibody-dependent cell-mediated cytotoxicity,ADCC),靶细胞SK-BR-3的裂解率达到47.1%;NitraTh-HER2疫苗能够产生抗原特异性的CTL效应,靶细胞SK-BR-3的裂解率达到14.6%。研究结果提示,DC-HIS小鼠模型为预测人类肿瘤疫苗的免疫原性提供了有效的方法。

    Abstract:

    Human immune system(HIS)mice are usually used to evaluate the ability of tumor vaccines to induce cytotoxic T lymphocyte(CTL)effects, but they failed to accurately reflect the ability of cancer vaccines to induce humoral immune responses. In this study, human peripheral blood mononuclear cells were isolated by density gradient centrifugation and co-transplanted into NCG mice with in vitro differentiated dendritic cells(DCs)to establish a DC-HIS mouse model. In DC-HIS mice, co-transplanted antigen-presenting cells(HLA-DR+CD11c+)could colonize the spleen of model mice. Moreover, co-transplantation of DCs significantly increased the proportion of activated human CD4+ T/CD8+ T cells and B cells in HIS mice, indicating that DC-HIS mice could better mimic the human immune responses. The immunogenicity of the targeted HER2 protein vaccine(NitraTh-HER2)was evaluated using the DCs-HIS mice. The results showed that the NitraTh-HER2 vaccine was able to induce the production of HER2-specific human IgG antibodies with a significant antibody-dependent cell-mediated cytotoxicity(ADCC)effect and the lysis rate of target cell SK-BR-3 reached 47. 1%. The NitraTh-HER2 vaccine was able to produce antigen-specific CTL effect, and the lysis rate of target cell SK-BR-3 reached 14. 6%. Taken together, the DC-HIS mouse model provides an effective method for predicting the immunogenicity of human tumor vaccines.

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江亮亮,江涛,罗建华,姚文兵,田浤.评价肿瘤疫苗免疫原性的新型人免疫系统小鼠模型[J].中国药科大学学报,2019,50(6):734-742.
Cite:JIANG Liangliang, JIANG Tao, LUO Jianhua, YAO Wenbing, TIAN Hong. A novel human immune system mice model for assessing the immunogenicity of cancer vaccines[J]. J China Pharm Univ,2019,50(6):734-742.

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  • 在线发布日期: 2019-12-31
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