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Development of gene therapy using chemokine that regulates the mobilization of dendritic cells in situ

使用趋化因子原位调节树突状细胞动员的基因治疗的开发

基本信息

批准号：
13671220
负责人：
TAKAYAMA Takuya
金额：
$ 2.43万
依托单位：
The University of Tokyo
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-13671220/
关键词：
dendritic cell Flt3L in vivo electroporation chemokine SLC dendritic cell chemokine CCR7 腫瘍免疫

项目摘要

1) Retroviral transduction of myeloid DC progenitors to overexpress TGF-beta is associated with marked impairment of their T-cell allostimulatory activity but with only modest prolongation of organ allograft survival. (ref. 1)2) We have established the genetically modified DC to regulate the immune response. We have also focused on Flt3-Ligand, a recently reported cytokine, is a stimulator for proliferation and differentiation of DC not only in vitro but in vivo. In this study, we evaluated the effects of FH3-Ligand on DC mobilization, proliferation, maturation and immune response using in vivo electroporation (IVE). After Flt3-Ligand trasfection using IVE, significantly high level of FH3-Ligand was detected in the serum during 10days after IVE. The frequency of DC both in spleen and bone marrow significantly was increased after Flt3-Ligand IVE when compared with those of control group. In mouse tumor model, FH3-Ligand IVE induced anti-tumor effect that was associated with proliferation and mobilization of DC. These results implied that Flt3-Ligand gene transfer using IVE could utilize to the clinical application for cancer gene therapy. (ref. 2)3) Secondary lymphoid-tissue chemokine (SLC), which is a member of CC chemokine, promotes the migration of mature dendritic cell (DC) expressed CCR7. In this study, we are going to examine the efficacy of SLC on DC mobilization in vivo and anti-tumor immunity by SLC gene modified tumor vaccination. (accepted as an oral presentation in The 103rd Annual Congress of Japan Surgical Society)

1)逆转录病毒转导髓系DC祖细胞过度表达TGF-β与其T细胞同种异体刺激活性的显著损害相关，但仅适度延长器官移植物存活。(ref. 1）2）我们已经建立了基因修饰的DC来调节免疫应答。Flt 3-Ligand是一种新近报道的细胞因子，在体外和体内均能刺激DC的增殖和分化。在这项研究中，我们评估了FH 3-配体对DC动员，增殖，成熟和免疫反应的影响，使用体内电穿孔（IVE）。经IVE转染Flt 3-Ligand后，在IVE后10天内血清中检测到明显高水平的Flt 3-Ligand。与对照组相比，Flt 3-Ligand IVE组小鼠脾脏和骨髓中DC的频率均显著增加。在小鼠肿瘤模型中，FH 3-Ligand IVE诱导的抗肿瘤作用与DC的增殖和动员有关。这些结果表明，利用IVE介导的Flt 3-Ligand基因转移可用于肿瘤基因治疗的临床应用。(ref. 2）3）次级淋巴组织趋化因子（SLC）是CC趋化因子的一员，其促进表达CCR 7的成熟树突状细胞（DC）的迁移。在本研究中，我们将通过SLC基因修饰的肿瘤疫苗来检测SLC对体内DC动员和抗肿瘤免疫的功效。（在日本外科学会第103届年会上接受口头报告）