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

通过激活 Th1 型辅助 T 细胞对胃肠癌进行免疫基因治疗。

基本信息

批准号：
09671281
负责人：
TAGAWA Masatoshi
金额：
$ 2.05万
依托单位：
Chiba Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671281/
关键词：
cytokine tumor immunology helper T cells gastrointestinal cancer gene therapy retrovirus

项目摘要

(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.

(1)我们研究了细胞因子介导的免疫反应是否积极参与了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细胞的分化成熟过程，而IL-15是由Th1型T细胞分泌的一种新的细胞因子。体内的致瘤性是通过将这些细胞因子产生细胞注入同基因或免疫受损的小鼠来测试的。所有的细胞因子产生细胞在不同的环境下都表现出抗肿瘤作用，特别是成熟的T细胞在每一种情况下都是不可或缺的。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，并观察到瘤周血管内皮细胞黏附分子的表达增强。相比之下，产生IL-18的肿瘤与产生IL-12的肿瘤具有相同的性质-产生干扰素伽玛的能力-不需要粒细胞或巨噬细胞来发挥抗肿瘤活性。自然杀伤细胞是产生IL-15的肿瘤的主要效应细胞。(2)IL-10是一种Th2型细胞因子，可抑制细胞免疫。IL-10基因在小鼠结肠癌细胞中的表达可抑制接种小鼠的全身免疫反应，这种抑制作用在成熟T细胞缺乏的情况下也可观察到。由Th1型细胞因子基因强制表达的Th1介导的免疫反应不能完全恢复这种免疫耐受。