Immuno-gene Therapy of Cancer by Interleukin-21 (IL-21)

白细胞介素-21（IL-21）由活化的CD 4 + T细胞分泌，支持成熟的T和B淋巴细胞增殖。该细胞因子与IL-15协同作用以促进自然杀伤（NK）细胞的扩增和成熟。IL-21的这些免疫调节功能已通过体外研究揭示;然而，IL-21在体内的生物学意义尚未完全阐明。在此，我们在转移性肝肿瘤的实验鼠模型中进行IL-21和/或IL-15的血管内转染。在高压下将IL-21和IL-15表达质粒静脉内注射到小鼠的尾静脉中，随后通过静脉内注射RLmale 1淋巴瘤细胞对其进行攻击。尽管模拟治疗和IL-21转染的小鼠在肝脏中发生转移性淋巴瘤，但IL-15基因转染显著减少了转移性肿瘤灶的数量。相比之下，当IL-21和IL-15基因共转染时，在80%的小鼠中实现了完全消退。细胞因子基因治疗也在静脉接种肿瘤细胞的小鼠中进行。40%的接受单次注射细胞因子基因混合物的小鼠成功地拒绝了预先建立的转移性淋巴瘤，并显示出超过300天的无瘤生存。IL-21显著提高了肿瘤接种小鼠脾脏中的细胞毒性T淋巴细胞（CTL）活性，而两种细胞因子以协同方式增强了自然杀伤细胞（NK）杀伤活性。干扰素-γ（IFN-γ）、IL-4和GM-CSF的血清浓度不受细胞因子治疗的显著影响。这些结果强烈表明，编码IL-21和IL-15的基因的共同施用诱导了强大的抗肿瘤免疫应答，而不引起任何严重的炎症不良反应，导致针对转移性恶性肿瘤的显著治疗功效。

Interleukin-21 (IL-21) is secreted from activated CD4+ T cells, supporting mature T and B lymphocyte proliferation. The cytokine synergizes with IL-15 to promotes expansion and maturation of natural killer (NK) cells. These immunomodulatory functions of IL-21 have been revealed by in vitro studies ; however, the biological implications of IL-21 in vivo have not been fully elucidated. Here, we performed intravascular transfection of IL-21 and/or IL-15 in an experimental murine model of metastatic liver tumors. 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. Although the mock-treated and IL-21-transfected mice developed metastatic lymphomas in the liver, IL-15 gene transfection significantly reduced the numbers of metastatic tumor foci. In contrast, when IL-21 and IL-15 genes were co-transfected, 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 pre-established metastatic lymphoma, and showed tumor-free survival for more than 300 days. IL-21 significantly elevated the cytotoxic T lymphocyte (CTL) activity in the spleens of tumor-inoculated mice, while the two cytokines augmented natural killer (NK) killing activity in a synergistic manner. Serum concentrations of interferon-gamma (IFN-gamma), IL-4, and GM-CSF were not significantly affected by the cytokine treatment. These results strongly suggest that the co-administration of genes encoding IL-21 and IL-15 induces powerful antitumor immune responses without causing any severe inflammatory adverse effects, resulting in drastic therapeutic efficacy against metastatic malignancies.