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

白介素21(IL-21)由活化的CD4+T细胞分泌，支持成熟T和B淋巴细胞的增殖。该细胞因子与IL-15协同作用，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被体外研究揭示；然而，IL-21在体内的生物学意义尚未完全阐明。在这里，我们在实验性小鼠转移性肝肿瘤模型中进行了IL-21和/或IL-15的血管内转染术。将IL-21和IL-15表达质粒高压注射到小鼠尾静脉，然后静脉注射RLMale1淋巴瘤细胞。尽管模型组和IL-21基因转染组小鼠肝脏发生了转移性淋巴瘤，但IL-15基因转染组显著减少了转移性肿瘤灶的数量。相反，当IL-21和IL-15基因共转染时，80%的小鼠完全消退。细胞因子基因治疗也在静脉接种肿瘤细胞的小鼠身上进行。在单次注射细胞因子基因混合物的小鼠中，40%的小鼠成功地拒绝了预先建立的转移性淋巴瘤，并表现出超过300天的无瘤生存。IL-21显著提高荷瘤小鼠脾细胞毒性T淋巴细胞(CTL)活性，两种细胞因子协同增强自然杀伤(NK)活性。细胞因子治疗对血清干扰素-γ、IL-4和GM-CSF浓度无显著影响。这些结果有力地表明，联合应用IL-21和IL-15基因可诱导强大的抗肿瘤免疫反应，而不会引起任何严重的炎症不良反应，从而对转移性恶性肿瘤具有显著的治疗效果。

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.