Hafner M, Zawatzky R, Hirtreiter C, Buurman W A, Echtenacher B, Hehlgans T, Männel D N
Department of Pathology/Tumor Immunology, University of Regensburg, 93042 Regensburg, Germany.
Cancer Res. 2001 Jul 15;61(14):5523-8.
The mechanisms involved in the antimetastatic effect of CpG-containing DNA were investigated in a mouse model of experimental metastasis. Tumor cell colony formation in lungs or livers of mice after i.v. inoculation with syngeneic fibrosarcoma or thymoma cells was determined. The i.v. injection of plasmid DNA or synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs before tumor cell application strongly inhibited metastasis. Because synthetic CpG-ODN was not directly tumor cytotoxic, the target cells for this CpG-ODN effect were determined. The cytotoxic activity on standard natural killer (NK) targets as well as on fibrosarcoma cells of splenic NK cells and NKT cell-containing liver mononuclear cells derived from CpG-ODN-treated mice was strongly enhanced. Participation of NK/NKT cells in the CpG-induced antimetastatic effect was demonstrated by reduction of the antimetastatic effect in mice depleted of NK/NKT cells and beta2-microglobulin-deficient mice. Neutralization of interleukin 12, interleukin 18, or IFN-gamma did not interfere with the CpG-induced antimetastatic effect. However, in sera of CpG-ODN-treated mice, high levels of IFN-alpha were detected, and in IFN-alpha/beta receptor-deficient mice, the CpG-ODN-induced antimetastatic effect was strongly reduced. These data indicate that CpG-ODNs activate NK/NKT cells for antimetastatic activity indirectly via IFN-alpha/beta receptor activation. The exploitation of the stimulatory activity of CpG-ODN for the innate immune system might be a useful strategy for antimetastatic therapy.
在实验性转移的小鼠模型中研究了含CpG的DNA的抗转移作用机制。通过静脉注射同基因纤维肉瘤或胸腺瘤细胞，测定小鼠肺或肝中的肿瘤细胞集落形成。在接种肿瘤细胞之前静脉注射含未甲基化CpG基序的质粒DNA或合成寡脱氧核苷酸（ODN）可强烈抑制转移。由于合成的CpG-ODN对肿瘤没有直接的细胞毒性，因此确定了这种CpG-ODN作用的靶细胞。来自CpG-ODN处理小鼠的脾NK细胞和含NKT细胞的肝单核细胞对标准自然杀伤（NK）靶细胞以及纤维肉瘤细胞的细胞毒活性显著增强。NK/NKT细胞缺失小鼠和β2-微球蛋白缺陷小鼠的抗转移作用降低，证明了NK/NKT细胞参与了CpG诱导的抗转移作用。白细胞介素12、白细胞介素18或干扰素-γ的中和并不干扰CpG诱导的抗转移作用。然而，在CpG-ODN处理小鼠的血清中检测到高水平干扰素-α，在干扰素-α/β受体缺陷小鼠中，CpG-ODN诱导的抗转移作用显著降低。这些数据表明，CpG-ODN通过激活干扰素-α/β受体间接激活NK/NKT细胞以发挥抗转移活性。利用CpG-ODN对先天免疫系统的刺激活性可能是抗转移治疗的一种有效策略。
