评价肿瘤疫苗免疫原性的新型人免疫系统小鼠模型

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

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。

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^+CD11 c^+) 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.