Augmentation of the migratory ability of DC-based vaccine into regional lymph nodes by efficient CCR7 gene transduction
Augmentation of the migratory ability of DC-based vaccine into regional lymph nodes by efficient CCR7 gene transduction
复制标题
DOI：
10.1038/sj.gt.3302358
复制
发表时间：
2005-01-01
期刊：
影响因子：
5.1
通讯作者：
Yamamoto, A
中科院分区：
文献类型：
--
作者：
Okada, N;Mori, N;Yamamoto, A
尽管基于树突状细胞（DC）的免疫疗法被认为是用于癌症治疗的有前景的方法，但是由于施用的DC向区域淋巴组织中的迁移能力差，需要大量的DC疫苗来有效致敏/激活免疫细胞。本研究应用RGD纤维突变型腺病毒载体（AdRGD）构建了CC趋化因子受体7（CCR 7）基因转导的DC疫苗（CCR 7/DCs），并对其免疫学特性和治疗效果进行了研究。CCR 7/DCs对CC趋化因子配体21（CCL 21）具有较强的趋化活性，在主要组织相容性复合物/共刺激分子表达水平和同种异体T细胞增殖刺激能力方面表现出与成熟DCs相似的免疫表型，同时保持了固有的内吞活性。重要的是，皮内注射到小鼠中的CCR 7/DC可以在引流淋巴结中比对照AdRGD应用的DC更有效地积累约5.5倍。同时表达内源性抗原和CCR 7基因的DC疫苗能够以较低的剂量在体内诱导出更有效的抗原特异性免疫应答，这反映了CCR 7/DC的这些特性。因此，具有向淋巴组织的正迁移能力的CCR 7/DC的应用可通过显著减少通过基于DC的免疫疗法实现有效治疗所需的DC疫苗剂量而有助于减少与DC疫苗制备相关的努力和成本。
Although dendritic cell (DC)-based immunotherapy is considered a promising approach for cancer treatment, a large quantity of DC vaccine is required for effective sensitization/ activation of immune cells because of the poor migratory ability of administered DCs into regional lymphoid tissue. In this study, we created a DC vaccine sufficiently transduced with CC chemokine receptor-7 gene (CCR7/DCs) by applying RGD fiber-mutant adenovirus vector (AdRGD), and investigated its immunological characteristics and therapeutic efficacy. CCR7/DCs acquired strong chemotactic activity for CC chemokine ligand-21 (CCL21) and exhibited an immunophenotype similar to mature DCs but not immature DCs with regard to major histocompatibility complex/costimulatory molecule-expression levels and allogenic T cell proliferation-stimulating ability, while maintaining inherent endocytotic activity. Importantly, CCR7/DCs injected intradermally into mice could accumulate in draining lymph nodes about 5.5-fold more efficiently than control AdRGD-applied DCs. Reflecting these properties of CCR7/DCs, DC vaccine genetically engineered to simultaneously express endogenous antigen and CCR7 could elicit more effective antigen-specific immune response in vivo using a lower dosage than DC vaccine transduced with antigen alone. Therefore, the application of CCR7/DCs having positive migratory ability to lymphoid tissues may contribute to reduction of efforts and costs associated with DC vaccine preparation by considerably reducing the DC vaccine dosage needed to achieve effective treatment by DC-based immunotherapy.