Nakui M, Ohta A, Sekimoto M, Sato M, Iwakabe K, Yahata T, Kitamura H, Koda T, Kawano T, Makuuchi H, Taniguchi M, Nishimura T
Section of Genetic Engineering, Research Center for Genetic Engineering and Cell Transplantation, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Clin Exp Metastasis. 2000;18(2):147-53. doi: 10.1023/a:1006715221088.
The combined therapeutic effect of natural killer T (NKT) cell ligand alpha-galactosylceramide (alpha-GalCer) and IL-12 against highly metastatic B16-BL6-HM melanoma cells was investigated. In comparison with a single administration of alpha-GalCer or IL-12, the combined treatment of tumor-bearing mice with alpha-GalCer plus IL-12 caused a super-induction of serum IFN-gamma levels, though alpha-GalCer-induced IL-4 production was rather inhibited. In parallel with the augmented IFN-gamma production, the natural killing activity against YAC-1 cells and syngeneic B16-BL6-HM melanoma was greatly augmented by the combined therapy. The major effector cells responsible for natural killing activity induced by alpha-GalCer plus IL-12 were enriched in both NK1.1+ TCRalphabeta+ NKT cells and NK1.1+ TCRalphabeta- NK cells. The preventing effect of alpha-GalCer or IL-12 alone against lung metastasis of B16-BL6-HM was also enhanced by the combination therapy. The antitumor activity of alpha-GalCer was totally abolished in NKT-deficient mice. However, IL-12-induced antitumor activity was not eliminated in NKT-deficient mice though it was inhibited by anti-asialo GM1 Ab treatment. These findings suggested that alpha-GalCer synergistically act with IL-12 to activate both NKT cells and NK cells, which may play a critical role in the strong prevention of distant tumor metastasis at early stages of tumor-bearing. These data will provide a novel tool for the prevention of tumor metastasis using NKT-specific ligands alpha-GalCer and IL-12.
研究了自然杀伤T（NKT）细胞配体α-半乳糖神经酰胺（α-GalCer）与白细胞介素-12（IL-12）联合对高转移性B16-BL6-HM黑色素瘤细胞的治疗效果。与单独给予α-GalCer或IL-12相比，用α-GalCer加IL-12联合治疗荷瘤小鼠可导致血清干扰素-γ（IFN-γ）水平的超诱导，尽管α-GalCer诱导的白细胞介素-4（IL-4）产生受到相当程度的抑制。与IFN-γ产生增加并行，联合治疗极大地增强了对YAC-1细胞和同基因B16-BL6-HM黑色素瘤的自然杀伤活性。负责α-GalCer加IL-12诱导的自然杀伤活性的主要效应细胞在NK1.1+TCRαβ+NKT细胞和NK1.1+TCRαβ-NK细胞中均有富集。联合治疗也增强了单独的α-GalCer或IL-12对B16-BL6-HM肺转移的预防作用。在NKT缺陷小鼠中，α-GalCer的抗肿瘤活性完全丧失。然而，IL-12诱导的抗肿瘤活性在NKT缺陷小鼠中并未消除，尽管它受到抗去唾液酸GM1抗体治疗的抑制。这些发现表明，α-GalCer与IL-12协同作用以激活NKT细胞和NK细胞，这可能在荷瘤早期对远处肿瘤转移的强力预防中起关键作用。这些数据将为使用NKT特异性配体α-GalCer和IL-12预防肿瘤转移提供一种新工具。
