Superior protective and therapeutic effects of IL-12 and IL-18 gene-transduced dendritic neuroblastoma fusion cells on liver metastasis of murine neuroblastoma
Superior protective and therapeutic effects of IL-12 and IL-18 gene-transduced dendritic neuroblastoma fusion cells on liver metastasis of murine neuroblastoma
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DOI：
10.4049/jimmunol.176.6.3461
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发表时间：
2006-03-15
影响因子：
4.4
通讯作者：
Kaneko, Michio
中科院分区：
文献类型：
--
作者：
Iinuma, Hisae;Okinaga, Kota;Kaneko, Michio
树突状细胞（dc）与肿瘤细胞融合疫苗具有诱导针对多种肿瘤Ags（包括未知肿瘤Ags）的免疫应答的优势。通过C1300神经母细胞瘤肝转移模型，我们评估了IL-12基因和/或IL-18基因转导融合细胞对C1300神经母细胞瘤的保护和治疗作用。通过将聚乙二醇与电穿孔相结合，改进了熔融方法，提高了负载效率。在接种LacZ基因修饰的融合细胞（fusion/LacZ）的A/J小鼠中，与DCs/LacZ、C1300/LacZ或两者的混合物（混合物/LacZ）相比，ifn - γ的产生和CTL活性显著增加。随着IL-12和IL-18基因转导进入融合细胞（fusion/IL-12/IL-18）， ifn - γ水平比其他融合组升高了5倍以上。NK细胞活性和CTL活性显著高于混合/LacZ、融合/LacZ、DC/LacZ和C1300/LacZ。在融合细胞疫苗的保护性和治疗性研究中，接种了融合/LacZ、融合/IL-12、融合/IL-18或融合/IL-12/IL-18的小鼠，与接种混合/LacZ、DCs/LacZ或C1300/LacZ的小鼠相比，肝脏转移率显著降低，生存率显著提高。特别是接种融合/IL-12/IL-18疫苗的小鼠表现出完全的保护作用和最高的治疗效果。本研究探讨了融合细胞负载效率的提高，提示IL-12和IL-18基因的引入对神经母细胞瘤肝转移具有极强的保护和治疗作用。
Fusion vaccine of dendritic cells (DCs) and tumor cells has the advantage of inducing an immune response against multiple tumor Ags, including unknown tumor Ags. Using the liver metastasis model of C1300 neuroblastoma cells, we assessed the protective and therapeutic effects of fusion cells transduced with the IL-12 gene and/or the IL-18 gene. Improving the fusion method by combining polyethylene glycol and electroporation increased loading efficiency. In the A/J mice vaccinated with fusion cells modified with the LacZ gene (fusion/LacZ), IFN-gamma production and CTL activity increased significantly compared with that of DCs/LacZ, C1300/LacZ, or a mixture of the two (mixture/LacZ). With the transduction of IL-12 and IL-18 genes into the fusion cells (fusion/IL-12/IL-18), the level of IFN-gamma increased more than five times that of other fusion groups. In addition, NK cell activity and CTL activity increased significantly compared with that of mixture/LacZ, fusion/LacZ, DC/LacZ, or C1300/LacZ. In the protective and therapeutic studies of fusion cell vaccine, mice vaccinated with fusion/LacZ, fusion/IL-12, fusion/IL-18, or fusion/IL-12/IL-18 showed a significant decrease in liver metastasis and a significant increase in survival compared with mice given a mixture/LacZ, DCs/LacZ, or C1300/LacZ. In particular, the mice receiving fusion/IL-12/IL-18 vaccine showed a complete protective effect and the highest therapeutic effects. The present study investigates the improved loading efficiency of fusion cells and suggests that the introduction of IL-12 and IL-18 genes can induce extremely strong protective and therapeutic effects on liver metastasis of neuroblastoma.