Gene therapy for gastrointestinal tumors using antigen presenting cells activated with gene transfer

使用通过基因转移激活的抗原呈递细胞进行胃肠道肿瘤的基因治疗

基本信息

批准号：
13671367
负责人：
TAGAWA Masatoshi
金额：
$ 2.62万
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：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671367/
关键词：
Gene therapy CD40 ligand CD40 dendritic cells protective immunity IL-12 CD86 Mig

项目摘要

We examined whether professional antigen presenting cells (dendritic cells) could be activated by the expression of CD40 ligand (CD40L) gene on tumors and antitumor immunity was subsequently induced. We retrovirally transduced tumors with the CD40L gene and established CD40L-expressed tumors whose MHC class I expression remained the same as that of parent tumors. Inoculation of the transduced cells into syngeneic mice revealed that growth of CD40L-expressed tumors was significantly retarded compared with that of parent tumors. Some of the mice completely rejected the CD40L-expressed tumors and the mice developed antigen-specific protective immunity. When nude mice were inoculated with the CD40L-expressed tumors, the growth was not different from that of parent tumors. In vitro culture of the CD40L-expressed tumors and bone marrow-derived dendritic cells showed that the cluster formation between dendritic cells and the CD40L-expressed but not parent tumors. The expression of MHC class II and activation marker CD86 on dendritic cells was upregulated after the coculture with CD40L-expressed but not parent tumors. The activated dendritic cells secreted IL-12, IL-18, IL-23 and Mig. These data collectively suggest that CD40L on tumors can activate dendritic cells through CD40/CD40L interaction and induce the expression of cytokines and chemokines, which play a crucial role in the generation of T cell-mediated antitumor effects.

我们研究了肿瘤上CD40配体（CD40L）基因的表达是否可以激活专职抗原呈递细胞（树突状细胞），并随后诱导抗肿瘤免疫。我们用CD40L基因逆转录病毒转导肿瘤，并建立了表达CD40L的肿瘤，其MHC I类表达与亲代肿瘤相同。将转导的细胞接种到同系小鼠中显示，与亲本肿瘤相比，表达CD40L的肿瘤的生长显着延迟。一些小鼠完全排斥表达CD40L的肿瘤，并且小鼠产生了抗原特异性保护性免疫。当裸鼠接种表达CD40L的肿瘤时，其生长与亲本肿瘤没有不同。 CD40L表达的肿瘤和骨髓源性树突状细胞的体外培养显示，树突状细胞与CD40L表达的肿瘤而非亲本肿瘤之间形成簇。与表达 CD40L 的肿瘤共培养后，树突状细胞上 MHC II 类和激活标记 CD86 的表达上调，但与亲本肿瘤不上调。活化的树突状细胞分泌IL-12、IL-18、IL-23和Mig。这些数据共同表明肿瘤上的CD40L可以通过CD40/CD40L相互作用激活树突状细胞并诱导细胞因子和趋化因子的表达，这在T细胞介导的抗肿瘤作用的产生中发挥着至关重要的作用。