权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Novel gene therapy by modulation of dendritic cells in vivo

通过体内树突状细胞调节的新型基因疗法

基本信息

批准号：
18591434
负责人：
TAKUYA Takayama
金额：
$ 2.44万
依托单位：
Japanese Foundation For Cancer Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591434/
关键词：
dendritic cell IL-18 FIt3L SLC CCL21

项目摘要

1, Combined mobilization and stimulation of tumor-infiltrating dendritic cells and natural killer cells with F1t3 ligand and IL-18 in vivo induces systemic anti-tumor immunityWe focused on the modulation of DCs in tumor microenvironment using F1t3 ligand (F1t3L) combined with IL-18. Tumor-inoculated mice were treated with in vivo electroporation (WE) of expression plasmids carrying cDNA of F1t3L. As combination therapy, mice in the other group were treated with intra-tumoral injection of adenoviral vector carrying IL-18 gene (Ad.IL-18). Significant anti-tumor effect was observed in mice treated with Ad.IL-18 alone when compared with that of control. In un-injected distant tumor, significant anti-tumor responses were observed only in the mice treated with combination therapy. Lymphoid cells in lymph nodes with combination therapy showed significant cytolytic activity against inoculated tumor cells and YAC-1 cells when compared with the ones in other groups. Tumor-infiltrating DCs with combination therapy showed higher CD86 expression and more potent allogeneic T cell stimulatory capacity. These results may suggest that local expression of IL-18 combined with in vivo DC mobilization with F1t3L is clinically applicable as a new strategy of DC immunotherapy. (Submitted for publication)2, The roles of CC-chemokine ligand 21 on T cell mediated anti-tumor immunityIn order to examine the underlying mechanism of CCL 21 on T cell mediated anti-tumor immunity, we developed an experimental approach of in vitro analysis of CCL 21. This in vitro analysis consisted of mature DCs and naive T cells purified from splenocytes which should express CCR7, and irradiated tumor cells in the presence or absence of recombinant CCL21 protein. CCL21 induced IFN-□ production from naive T cells and this effect needed the direct cell contact between DCs and T cells, and promoted the generation of tumor-specific CTLs.

1、F1t3配体和IL-18在体内联合动员和刺激肿瘤浸润性树突状细胞和自然杀伤细胞诱导全身抗肿瘤免疫我们重点研究了F1t3配体（F1t3L）联合IL-18对肿瘤微环境DCs的调节。用携带F1t3L cDNA的表达质粒在体内电穿孔（WE）处理肿瘤接种小鼠。作为联合治疗，另一组小鼠在瘤内注射携带IL-18基因的腺病毒载体（Ad.IL-18）。Ad对小鼠有明显的抗肿瘤作用。单独IL-18与对照组比较。在未注射的远处肿瘤中，仅在联合治疗的小鼠中观察到显著的抗肿瘤反应。与其他治疗组相比，联合治疗组淋巴结淋巴样细胞对接种肿瘤细胞和YAC-1细胞表现出明显的细胞溶解活性。联合治疗的肿瘤浸润性dc显示出更高的CD86表达和更强的同种异体T细胞刺激能力。这些结果可能提示IL-18局部表达联合体内DC动员F1t3L作为DC免疫治疗的新策略在临床上是可行的。2、cc趋化因子配体21在T细胞介导的抗肿瘤免疫中的作用为了探究CCL 21在T细胞介导的抗肿瘤免疫中的作用机制，我们建立了CCL 21体外分析的实验方法。这项体外分析包括成熟的dc和从表达CCR7的脾细胞中纯化的幼稚T细胞，并在存在或不存在重组CCL21蛋白的情况下照射肿瘤细胞。CCL21诱导幼稚T细胞产生IFN-□，这种作用需要dc和T细胞之间的直接细胞接触，并促进肿瘤特异性ctl的产生。