The Gade Institute, University of Bergen, Norway.
BMC Immunol. 2011 Jan 5;12:2. doi: 10.1186/1471-2172-12-2.
Design of tumour specific immunotherapies using the patients' own dendritic cells (DC) is a fast advancing scientific field. The functional qualities of the DC generated in vitro are critical, and today's gold standard for maturation is a cytokine cocktail consisting of IL-1β, IL-6, TNF-α and PGE2 generating cells lacking IL-12p70 production. OK432 is an immunotherapeutic agent derived from killed Streptococcus pyogenes that has been used clinically to treat malignant and benign neoplasms for decades.
In this study, we analysed the effects of OK432 on DC maturation, DC migration, cytokine and chemokine secretion as well as T-cell stimulatory capacity, and compared it to the cytokine cocktail alone and combinations of OK432 with the cytokine cocktail.
OK432 induced a marked up-regulation of CD40 on the cell surface as well as a strong inflammatory response from the DC with significantly more secretion of 19 different cytokines and chemokines compared to the cytokine cocktail. Interestingly, secretion of IL-15 and IL-12p70 was detected at high concentrations after maturation of DC with OK432. However, the OK432 treated DC did not migrate as well as DC treated with cytokine cocktail in a transwell migration assay. During allogeneic T-cell stimulation OK432 treated DC induced proliferation of over 50 percent of CD4 and 30 percent of CD8 T-cells for more than two cell divisions, whereas cytokine cocktail treated DC induced proliferation of 12 and 11 percent of CD4 and CD8 T-cells, respectively.
The clinically approved compound OK432 has interesting properties that warrants its use in DC immunotherapy and should be considered as a potential immunomodulating agent in cancer immunotherapy.
利用患者自身树突状细胞（DC）设计肿瘤特异性免疫疗法是一个快速发展的科学领域。体外生成的 DC 的功能质量至关重要，目前成熟的金标准是由 IL-1β、IL-6、TNF-α 和 PGE2 组成的细胞因子鸡尾酒，该鸡尾酒可生成缺乏 IL-12p70 产生的细胞。OK432 是一种源自死链珠菌的免疫治疗剂，已在临床上用于治疗恶性和良性肿瘤数十年。
在这项研究中，我们分析了 OK432 对 DC 成熟、DC 迁移、细胞因子和趋化因子分泌以及 T 细胞刺激能力的影响，并将其与细胞因子鸡尾酒单独以及 OK432 与细胞因子鸡尾酒的组合进行了比较。
与细胞因子鸡尾酒相比，OK432 诱导细胞表面 CD40 的显著上调以及 DC 的强烈炎症反应，导致 19 种不同的细胞因子和趋化因子的分泌显著增加。有趣的是，在用 OK432 成熟 DC 后检测到高浓度的 IL-15 和 IL-12p70 分泌。然而，在用 OK432 处理的 DC 中，在 Transwell 迁移测定中，其迁移能力不如用细胞因子鸡尾酒处理的 DC。在同种异体 T 细胞刺激过程中，OK432 处理的 DC 诱导超过 50%的 CD4 和超过 30%的 CD8 T 细胞增殖超过两个细胞分裂，而细胞因子鸡尾酒处理的 DC 诱导分别为 12%和 11%的 CD4 和 CD8 T 细胞增殖。
临床批准的 OK432 化合物具有有趣的特性，值得在 DC 免疫疗法中使用，并且应该被视为癌症免疫疗法中潜在的免疫调节剂。
