Intravesical Interleukin-15 Gene Therapy in an Orthotopic Bladder Cancer Model
Intravesical Interleukin-15 Gene Therapy in an Orthotopic Bladder Cancer Model
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DOI：
10.1089/hum.2011.013
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发表时间：
2011-11-01
影响因子：
4.2
通讯作者：
Oya, Mototsugu
中科院分区：
文献类型：
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作者：
Matsumoto, Kazuhiro;Kikuchi, Eiji;Oya, Mototsugu
已知白细胞介素-15（IL-15）刺激CD 8（+）T细胞和自然杀伤细胞的增殖，并且还有助于维持记忆性CD 8（+）T细胞，这表明它可能在膀胱癌的细胞因子治疗中具有价值。在本实验中，我们测试了膀胱内脂质体IL-15基因递送的效率及其在小鼠原位膀胱癌模型中的抗肿瘤作用。我们通过尿道将5 x 10（5）个MBT-2细胞植入雌性C3 H/HeN小鼠体内，建立了原位膀胱癌模型。小鼠接受重复的膀胱内基因传递，经尿道注射脂质体介导的质粒（5 μ g）。在第23天，仅接受培养基的组、β-半乳糖苷酶基因递送对照组和IL-15基因治疗组的膀胱重量分别为196 +/-36 mg、201 +/-35 mg和96 +/-29 mg（p < 0.05），证明了膀胱内IL-15基因治疗在该模型中的抗肿瘤作用。经IL-15基因质粒灌注的膀胱组织中，组织学分析显示肿瘤周围诱导了许多炎性细胞。免疫组化分析证实肿瘤巢周围主要为CD 8（+）T细胞浸润。膀胱内IL-15基因治疗后，存活小鼠中再激发的皮下MBT-2细胞的生长通过肿瘤特异性细胞毒性T淋巴细胞再次受到抑制，尽管相同小鼠中新植入的FM 3A细胞没有被排斥。提示IL-15基因治疗可能成为膀胱癌一种新的辅助治疗手段。
Interleukin-15 (IL-15) is known to stimulate the proliferation of CD8(+) T-cells and natural killer cells, and also to help to maintain memory CD8(+) T cells, suggesting that it may be of value in cytokine treatment of bladder cancer. In this experiment, we tested the efficiency of intravesical liposomal IL-15 gene delivery and its antitumor effect in a mouse orthotopic bladder cancer model. We established an orthotopic bladder cancer model by implanting 5 x 10(5) MBT-2 cells into female C3H/HeN mice through the urethra. The mice received repeated intravesical gene delivery injected with liposome-mediated plasmids (5 mu g) transurethrally. On day 23, the bladder weights in the group receiving medium alone, the beta-galactosidase gene delivery control group, and the IL-15 gene therapy group were 196 +/- 36 mg, 201 +/- 35 mg, and 96 +/- 29 mg, respectively (p < 0.05), demonstrating the antitumor effect of intravesical IL-15 gene therapy in this model. In the bladders treated with IL-15 gene plasmid instillation, histological analysis revealed that many inflammatory cells were induced around the tumors. Immunohistochemical analysis confirmed that there was predominant infiltration of CD8(+) T cells around the tumor nest. After the intravesical IL-15 gene therapy, the growth of rechallenged subcutaneous MBT-2 cells in surviving mice was inhibited again via tumor-specific cytotoxic T lymphocytes, although newly implanted FM3A cells in the same mice were not rejected. The present findings indicate that IL-15 gene therapy may be a promising new adjuvant therapy for bladder cancer.