IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice
IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice
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DOI：
10.4049/jimmunol.173.11.6635
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发表时间：
2004-12-01
影响因子：
4.4
通讯作者：
Maehara, Y
中科院分区：
文献类型：
--
作者：
Harada, N;Shimada, M;Maehara, Y
器官移植的免疫抑制治疗是控制排斥反应的关键。当肝移植作为肝细胞癌（HCC）的治疗方法时，复发性HCC是最致命的并发症之一。在这项研究中，我们表明，肿瘤内小鼠IL-12（mIL-12）基因治疗有可能成为一种有效的治疗恶性肿瘤的免疫抑制。C3 H小鼠（H-2（kappa）），腹膜内注射FK 506（3 mg/kg），是s.c.植入2.5 × 10（6）MH 134细胞（H-2（kappa）），并使用mIL-12质粒DNA通过电穿孔介导的基因疗法治疗已建立的HCC。与HCC转移的对照pCAGGS质粒相比，mIL-12的瘤内基因转移升高了瘤内mIL-12、IFN-γ和IFN-γ诱导蛋白-10，显著减少了微血管的数量并抑制了HCC的生长。免疫抑制小鼠中肿瘤生长的抑制与免疫活性小鼠中mIL-12基因治疗的抑制相当。肿瘤内mIL-12基因治疗增强了淋巴细胞向肿瘤的浸润，甚至在FK 506下也引起了MH 134特异性CTL应答。在针对MH 134的mIL-12基因治疗期间，FK 506的剂量足以预防作为移植物的远距离同种异体皮肤移植物（BALB/c小鼠，H-2（d））和肿瘤B7-p815（H-2（d））的排斥反应。Ab介导的耗竭研究表明，mIL-12对肿瘤生长、新生血管形成和自发性肺转移的抑制几乎完全依赖于NK细胞，部分依赖于T细胞。结果提示，瘤内注射mIL-12基因治疗不仅是治疗肝移植后肝癌复发的有效方法，而且对移植器官免疫抑制患者的实体性恶性肿瘤也有一定的疗效。
Immunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2(kappa)), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 x 10(6) MH134 cells (H-2(kappa)) and we treated the established HCC with electroporation-mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-gamma, and IFN-gamma-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2(d)) and tumors, B7-p815 (H-2(d)) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.