Nakano Hiroshi, Kishida Tsunao, Asada Hidetsugu, Shin-Ya Masaharu, Shinomiya Takashi, Imanishi Jiro, Shimada Taketoshi, Nakai Shigeru, Takeuchi Minoru, Hisa Yasuo, Mazda Osam
Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
J Gene Med. 2006 Jan;8(1):90-9. doi: 10.1002/jgm.817.
Interleukin-21 (IL-21) plays important roles in the regulation of T, B, and natural killer (NK) cells. We hypothesized that the cytokine may provide a novel immunotherapy strategy for cancer by stimulating both Th1 and Th2 immune responses. In this context, antitumor immunity induced by IL-21 was examined in mice bearing subcutaneous head and neck squamous cell carcinomas (HNSCC).
A plasmid vector encoding murine IL-21 was injected intravenously into mice with pre-established HNSCC tumors, either alone or in combination with a vector construct expressing IL-15. Cytotoxic T lymphocyte (CTL) and NK killing activities were evaluated by chrome release assays, while HNSCC-specific antibody was examined by flow cytometry and ELISA.
Significant antitumor effects were obtained by repeated transfection with either the IL-21 or the IL-15 gene. Co-administration of both cytokine genes resulted in increased suppression of tumor growth, significantly prolonging the survival periods of the animals. Thirty percent of the tumor-bearing mice that received the combination therapy survived for more than 300 days, completely rejecting rechallenge with the tumor at a distant site. IL-21 induced significant elevation of HNSCC-specific CTL activity, while IL-21 and IL-15 augmented NK activity in an additive manner. IL-21 gene transfer also promoted the production of tumor-specific IgG.
In vivo transduction of the IL-21 gene elicits powerful antitumor immunity, including both humoral and cellular arms of the immune response, and results in significant suppression of pre-established HNSCC. Co-transfer of the IL-15 gene further improved the therapeutic outcome, mainly by augmenting NK tumoricidal activity. The biological effects of IL-21 may be in sharp contrast to those of conventional Th1 and Th2 cytokines, suggesting intriguing implications of this cytokine for the classical concept of Th1 vs. Th2 paradigm.
白细胞介素-21（IL-21）在T细胞、B细胞和自然杀伤（NK）细胞的调节中发挥重要作用。我们推测，这种细胞因子可能通过刺激Th1和Th2免疫反应为癌症提供一种新的免疫治疗策略。在此背景下，我们在患有皮下头颈部鳞状细胞癌（HNSCC）的小鼠中研究了IL-21诱导的抗肿瘤免疫。
将编码小鼠IL-21的质粒载体静脉注射到已建立HNSCC肿瘤的小鼠体内，单独注射或与表达IL-15的载体构建体联合注射。通过铬释放试验评估细胞毒性T淋巴细胞（CTL）和NK杀伤活性，同时通过流式细胞术和ELISA检测HNSCC特异性抗体。
用IL-21或IL-15基因重复转染可获得显著的抗肿瘤效果。两种细胞因子基因联合给药可增强对肿瘤生长的抑制作用，显著延长动物的生存期。接受联合治疗的荷瘤小鼠中有30%存活超过300天，完全排斥远处部位肿瘤的再次攻击。IL-21显著提高了HNSCC特异性CTL活性，而IL-21和IL-15以相加的方式增强了NK活性。IL-21基因转移还促进了肿瘤特异性IgG的产生。
IL-21基因的体内转导引发了强大的抗肿瘤免疫，包括免疫反应的体液和细胞分支，并导致对已建立的HNSCC的显著抑制。IL-15基因的共转移进一步改善了治疗效果，主要是通过增强NK杀瘤活性。IL-21的生物学效应可能与传统的Th1和Th2细胞因子的效应形成鲜明对比，这表明这种细胞因子对Th1与Th2范式的经典概念具有有趣的意义。
