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

1)逆转录病毒转导髓系DC前体细胞过度表达转化生长因子-β与其T细胞同种异体刺激活性显著受损有关，但仅适度延长器官移植存活时间。(参考文献)1)2)我们建立了转基因DC来调节免疫反应。我们还关注了最近报道的一种细胞因子Flt3-Ligand，它不仅在体外而且在体内都是DC增殖和分化的刺激因子。在本研究中，我们利用体内电穿孔技术(IVE)评价了FH3-Ligand对DC动员、增殖、成熟和免疫应答的影响。用IVE转导Flt3-Ligand后，在IVE后10天内，血清中FH3-Ligand水平显著升高。与对照组相比，Flt3-Ligand IVE组小鼠脾和骨髓DC的频率均显著增加。在小鼠肿瘤模型中，FH3-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，IVE介导的Flt3-Ligand基因转移可应用于肿瘤基因治疗的临床应用。(参考文献)2)次级淋巴组织趋化因子(SLC)是CC趋化因子的一员，可促进表达CCR7的成熟树突状细胞(DC)的迁移。本研究旨在探讨SLC基因修饰的肿瘤疫苗对DC的体内动员和抗肿瘤免疫的影响。(被日本外科学会第103届年会接受为口头陈述)

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)