Immune gene therapy for gastrointestinal cancer by activation Th1-type helper T cells.

(1)研究细胞因子介导的免疫反应是否积极参与胃肠道肿瘤的抗肿瘤作用。为了增强在抗肿瘤免疫中起关键作用的th1型T细胞的活性，我们在小鼠结肠癌细胞中引入了几种细胞因子基因（IL-12、IL-15和IL-18）。IL-12和IL-18介导th1型T细胞的分化和成熟过程，而IL-15是一种新的细胞因子，由th1型T细胞分泌。通过将这些细胞因子产生细胞注入同基因或免疫功能低下的小鼠体内来测试体内致瘤性。所有细胞因子产生细胞在各种情况下都显示出抗肿瘤作用，特别是我们发现成熟T细胞在每种情况下都是必不可少的。在产生IL-12的细胞中，粒细胞和/或巨噬细胞也参与了抗肿瘤活性，并且观察到肿瘤周围内皮中粘附分子的表达增强。相比之下，产生IL-18的肿瘤具有与产生IL-12的肿瘤相同的特性——产生干扰素γ的能力，不需要粒细胞或巨噬细胞来发挥其抗肿瘤活性。自然杀伤细胞是产生IL-15肿瘤的主要效应细胞。(2) IL-10是一种th2型细胞因子，被认为具有抑制细胞免疫的作用。小鼠结肠癌细胞中IL-10基因的表达积极抑制接种小鼠的全身免疫反应，并且在成熟T细胞缺陷条件下也观察到这种抑制。通过强制表达th1型细胞因子基因而引起的th1介导的免疫反应，并不能完全恢复这种免疫耐受。

(1) We examined whether cytokine-mediated immune responses are actively involved in antitumor effects on gastrointestinal tumors. To augment the activity of Th1-type T cells which play crucial roles in antitumor immunity, we introduced several cytokine genes (IL-12, IL-15 and IL-18) in murine colon carcinoma cells. IL-12 and IL-18 mediate differentiation and maturation steps of Th1-type T cells, and IL-15, a novel cytokine, are secreted from Th1-type T cells. In vivo tumorigenicity was tested by inculating these cytokine producer cells into syngeneic or immunocompromised mice. All the cytokine producer cells showed antitumor effect in various circumstances, in particular, we showed that mature T cells were indispensable in every case. In the case of IL-12 producing cells, granulocytes and/or macrophages were also involved in the antitumor activity and enhanced expression of adhesion molecules in the endothelium of peritumoral regions was observed. In contrast, IL-18 producing tumors which shares the same properties-ability to produce interferon gammma-as IL-12 producing tumors, did not require granulocytes or macrophages for their antitumor activities. Natural killer cells are primary effector cells in IL-15 producing tumors. (2) IL-10, a Th2-type cytokine, is regarded to inhibit cellular immunity.Expression of IL-10 gene in murine colon carcinoma cells actively suppressed systemic immune responses in the inoculated mice and this suppression was also observed in mature T cells-deficient conditions. Th1-mediated immune responses, which is brough by forced expression of Th1-type cytokine genes, could not fully restore this immune tolerance.