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

(1)我们研究了马槟榔碱介导的免疫应答是否积极参与对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Th 1型T细胞的活性，我们将几种细胞因子基因（IL-12、IL-15和IL-18）导入小鼠结肠癌细胞中。IL-12和IL-18介导Th 1型T细胞的分化和成熟步骤，IL-15是一种新的细胞因子，由Th 1型T细胞分泌。通过将这些细胞因子产生细胞接种到同基因或免疫受损小鼠中来测试体内致瘤性。所有的细胞因子产生细胞在不同的情况下显示出抗肿瘤作用，特别是，我们表明，成熟的T细胞在每种情况下都是不可缺少的。在IL-12产生细胞的情况下，粒细胞和/或巨噬细胞也参与抗肿瘤活性，并且观察到肿瘤周围区域的内皮中粘附分子的表达增强。相反，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，其抗肿瘤活性不需要粒细胞或巨噬细胞。自然杀伤细胞是产生IL-15的肿瘤中的主要效应细胞。(2)IL-10是一种Th 2型细胞因子，被认为具有抑制细胞免疫的作用，在小鼠结肠癌细胞中表达IL-10基因可有效抑制接种小鼠的全身免疫应答，这种抑制作用在成熟T细胞缺乏的情况下也能观察到。Th 1型细胞因子基因的强制表达所引起的Th 1介导的免疫应答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.