Fujimoto T, Duda R B, Szilvasi A, Chen X, Mai M, O'Donnell M A
Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
J Immunol. 1997 Jun 15;158(12):5619-26.
Streptococcal preparation OK-432 is a bacterial immunopotentiator extensively used in Japan for adjuvant cancer therapy. Using a C57BL/6 mouse model, OK-432 was found to induce multiple cytokines including the Th1 polarizing cytokine IL-12. Expression of IL-12 protein by murine splenocytes was restricted to macrophages and B cells and led to high levels of IFN-gamma production from both CD4+ and CD8+ T cells. Of the Th2 cytokines IL-4 and IL-10, only IL-10 protein was detected and originated primarily from the adherent cell population. Its expression was delayed relative to IL-12. A similar pattern of cytokine induction was observed from human PBMCs. OK-432-driven IFN-gamma production was inhibited by anti-IL-12 Ab, anti-IL-2 Ab, anti-TNF-alpha Ab, and anti-IL-2R alpha Ab, suggesting that IFN-gamma production from Th1 cells is induced by the cooperation action of these cytokines through the IL-2R alpha pathway. When compared with another widely used immunopotentiator bacillus Calmette-Guérin (BCG), OK-432 was a stronger IL-12 and IFN-gamma inducer. Furthermore, the mechanism of IFN-gamma induction by OK-432 differed from BCG in that coincident granulocyte-macrophage CSF and IL-1 expression played little to no role. These results suggest that OK-432 is a potent multicytokine inducer, specifically a strong inducer of IL-12, and that OK-432 may exert its antitumor effect by promoting a Th1-dominant state.
链球菌制剂OK-432是一种细菌免疫增强剂，在日本广泛用于辅助癌症治疗。使用C57BL/6小鼠模型，发现OK-432可诱导多种细胞因子，包括Th1极化细胞因子IL-12。小鼠脾细胞中IL-12蛋白的表达仅限于巨噬细胞和B细胞，并导致CD4+和CD8+ T细胞产生高水平的IFN-γ。在Th2细胞因子IL-4和IL-10中，仅检测到IL-10蛋白，且主要来源于贴壁细胞群体。其表达相对于IL-12有所延迟。在人外周血单核细胞中也观察到类似的细胞因子诱导模式。抗IL-12抗体、抗IL-2抗体、抗TNF-α抗体和抗IL-2Rα抗体可抑制OK-432驱动的IFN-γ产生，这表明Th1细胞产生的IFN-γ是由这些细胞因子通过IL-2Rα途径的协同作用诱导产生的。与另一种广泛使用的免疫增强剂卡介苗（BCG）相比，OK-432是更强的IL-12和IFN-γ诱导剂。此外，OK-432诱导IFN-γ的机制与BCG不同，因为同时存在的粒细胞-巨噬细胞集落刺激因子和IL-1表达几乎没有作用。这些结果表明，OK-432是一种有效的多细胞因子诱导剂，特别是IL-12的强诱导剂，并且OK-432可能通过促进Th1主导状态发挥其抗肿瘤作用。
