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）我们检查了细胞因子介导的免疫反应是否积极参与抗肿瘤对胃肠道肿瘤的影响。为了增加在抗肿瘤免疫中起着至关重要的作用的Th1型T细胞的活性，我们在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细胞的分化和成熟步骤，而新型细胞因子IL-15分泌于Th1型T细胞。通过将这些细胞因子生产剂细胞灌输到合成性或免疫功能低下的小鼠中来测试体内肿瘤性。在各种情况下，所有细胞因子生产细胞均表现出抗肿瘤作用，我们表明成熟的T细胞在每种情况下都是必不可少的。在IL-12产生的细胞的情况下，粒细胞和/或巨噬细胞也参与了抗肿瘤活性，并且观察到周围肿瘤区域内皮中粘附分子的表达增强。相反，IL-18产生具有相同特性的肿瘤，可产生干扰素γ-AS IL-12产生肿瘤，不需要粒细胞或巨噬细胞来进行抗肿瘤活性。天然杀伤细胞是IL-15产生肿瘤的主要效应细胞。（2）IL-10是一种Th2型细胞因子，被认为是抑制细胞免疫。在鼠结肠癌癌细胞中IL-10基因表达在接种的小鼠中积极抑制了全身免疫反应，并且在成熟T细胞缺乏成熟的T细胞缺陷条件下也观察到了这种抑制。 Th1介导的免疫反应是通过强迫表达Th1型细胞因子基因而进行的，无法完全恢复这种免疫耐受性。