Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic lymphoma
Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic lymphoma
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DOI：
10.1016/s1525-0016(03)00222-3
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发表时间：
2003-10-01
影响因子：
12.4
通讯作者：
Mazda, O
中科院分区：
文献类型：
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作者：
Kishida, T;Asada, H;Mazda, O
IL-21支持成熟T细胞和B细胞的增殖，并与IL-15协同促进自然杀伤细胞（NK）的扩增和成熟。然而，IL-21在体内的生物学意义尚未完全阐明。将IL-21和IL-15表达质粒在高压下静脉注射到小鼠尾静脉，随后静脉注射rlmal1淋巴瘤细胞攻毒。il - 15基因转染显著减少肝脏转移性肿瘤灶的数量。相比之下，当同时转染IL21和IL15基因时，80%的小鼠实现了完全回归。细胞因子基因治疗也在静脉注射肿瘤细胞的小鼠中进行。接受细胞因子基因混合物单次注射的小鼠中，有40%成功地拒绝了预先建立的转移性淋巴瘤，并显示无肿瘤生存超过300天。IL-21显著提高肿瘤接种小鼠脾脏细胞毒性T淋巴细胞活性，两种细胞因子协同增强NK杀伤活性。这些结果强烈表明，IL-21和IL-15的共递送引起了强大的抗肿瘤免疫反应，导致对转移性肿瘤的显着治疗效果。
IL-21 supports proliferation of mature T and B cells and facilitates expansion and maturation of natural killer (NK) cells in synergy with IL-15. However, the biological implications of IL-21 in vivo have not been fully elucidated. IL-21 and IL-15 expression plasmids were intravenously injected under high pressure into the tail veins of mice, which were subsequently challenged by an intravenous injection of RLmale1 lymphoma cells. The IL15 gene transfection significantly reduced the numbers of metastatic tumor foci in the liver. In contrast, when IL21 and IL15 genes were cotransfected, complete regression was achieved in 80% of the mice. The cytokine gene therapy was also performed in mice that had been intravenously inoculated with the tumor cells. Forty percent of mice that received a single injection of a mixture of cytokine genes successfully rejected the preestablished metastatic lymphoma and showed tumor-free survival for more than 300 days. IL-21 significantly elevated the cytotoxic T lymphocyte activity in the spleens of tumor-inoculated mice, while the two cytokines augmented NK killing activity in a synergistic manner. These results strongly suggest that the codelivery of IL-21 and IL-15 elicits powerful antitumor immune responses, resulting in marked therapeutic efficacy against metastatic tumors.