Dendritic cells stimulated with a bacterial product, OK-432, efficiently induce cytotoxic T lymphocytes specific to tumor rejection peptide.
Dendritic cells stimulated with a bacterial product, OK-432, efficiently induce cytotoxic T lymphocytes specific to tumor rejection peptide.
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发表时间：
2003-07
期刊：
影响因子：
11.2
通讯作者：
S. Nakahara;T. Tsunoda;Toshiyuki Baba;S. Asabe;H. Tahara
中科院分区：
文献类型：
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作者：
S. Nakahara;T. Tsunoda;Toshiyuki Baba;S. Asabe;H. Tahara
树突状细胞（Dendritic cells，DCs）是一种高效的抗原提呈细胞，近年来被应用于肿瘤抗原表位肽的免疫治疗。这种策略的临床试验的累积结果表明，所应用的DC的成熟度对疫苗接种的结果具有显著影响。在这里，我们研究了青霉素杀死的化脓性链球菌（OK-432）对DC成熟和功能的影响，包括诱导CTL。使用粒细胞巨噬细胞集落刺激因子和白细胞介素（IL）-4从外周血产生的DC显示与未成熟DC（iDC）一致的免疫表型。将这些iDC与单独的培养基、肿瘤坏死因子α、脂多糖或OK-432进一步孵育。免疫表型分析显示，经OK-432刺激的DCs（OK-DCs）与未经刺激的DCs相比，CD 83的表达显著增加。此外，OK-DCs与其他刺激的DCs相比显示出显著更高的IL-12和IFN-γ的产生。这些结果表明，OK-432刺激iDC具有成熟表型并产生显著量的T辅助细胞1型细胞因子。为了检测OK-DCs诱导特异性CTL的效力，使用源自癌胚抗原的肿瘤排斥肽作为模型抗原。HLA-四聚体分析显示，OK-DCs以高频率诱导了有效的CTL。这些结果表明OK-432有效地刺激DC而不干扰脉冲肽的呈递。此外，OK-432不通过指示细胞系统中的Toll样受体2或Toll样受体4激活核因子κ B;然而，它通过DC上的β（2）整联蛋白系统诱导IL-12产生。这些结果有力地表明，OK-432可以应用于开发一种有效的癌症疫苗，使用肿瘤排斥肽脉冲的DC。
Dendritic cells (DCs) are potent antigen-presenting cells, which have recently been applied for cancer immunotherapy using epitope peptides. Accumulating results of the clinical trials of such a strategy suggest that maturity of the applied DCs has a significant impact on the outcome of the vaccination. Here we examined the effects of penicillin-killed Streptococcus pyogenes (OK-432) on DC maturation and functions including induction of CTLs. DCs generated from peripheral blood using granulocyte macrophage colony-stimulating factor and interleukin (IL)-4 showed immunophenotypes consistent with immature DCs (iDCs). These iDCs were further incubated with medium alone, tumor necrosis factor alpha, lipopolysaccharide, or OK-432. The immunophenotypical analysis showed DCs stimulated with OK-432 (OK-DCs) possessed significantly higher expression of CD83 compared with unstimulated DCs. Furthermore, OK-DCs showed significantly higher production of IL-12 and IFN-gamma compared with DCs with other stimulations. These results indicate that OK-432 stimulates iDCs to have a mature phenotype and to produce a significant amount of T-helper 1-type cytokines. To examine the potency of OK-DCs on the induction of specific CTLs, the tumor rejection peptide derived from carcinoembryonic antigen was used as a model antigen. The HLA-tetramer assay showed that potent CTL was induced with OK-DCs at high frequency. These results indicate that OK-432 efficiently stimulates DCs without interfering with the presentation of pulsed peptide. Furthermore, OK-432 does not activate nuclear factor kappaB through Toll-like receptor 2 or Toll-like receptor 4 in the indicator cell system; however, it induces IL-12 production through the beta(2) integrin system on DCs. These results strongly suggest that OK-432 could be applied to develop an efficient cancer vaccine using DCs pulsed with tumor rejection peptides.