Divergent therapeutic and immunologic effects of oligodeoxynucleotides with distinct CpG motifs
Divergent therapeutic and immunologic effects of oligodeoxynucleotides with distinct CpG motifs
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DOI：
10.4049/jimmunol.167.9.4878
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发表时间：
2001-11-01
影响因子：
4.4
通讯作者：
Weiner, GJ
中科院分区：
文献类型：
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作者：
Ballas, ZK;Krieg, AM;Weiner, GJ
非甲基化CpG基序的免疫刺激性寡脱氧核苷酸（ODN）是天然免疫和获得性免疫的有效诱导剂。最初看来，单一类型的最佳CpG基序将在所有应用中起作用。我们现在报告说，特定的CpG ODN基序可以显着不同的能力，以诱导个体的免疫效应，这些差异影响其在不同的肿瘤模型中的抗肿瘤活性。特别地，具有与聚（G）尾组合的嵌合骨架的独特类型的CpG基序是NK裂解活性的有效诱导剂，但对细胞因子分泌或B细胞增殖几乎没有影响。一种这样的NK优化的CpG ODN（1585）可以诱导小鼠中已建立的黑素瘤的消退。令人惊讶的是，对于活化B细胞和Th 1样细胞因子表达优化的CpG ODN（ODN 1826）没有观察到这样的治疗效果。CpG 1585在黑色素瘤中的治疗作用需要NK细胞的存在，而不是T或B细胞的存在，并且与肿瘤特异性记忆反应的诱导无关。相比之下，CpG 1826，而不是CpG 1585，是有效的诱导退化的EL 4小鼠淋巴瘤;这种排斥反应与诱导记忆反应，虽然NK细胞是必要的，他们是不够的。这些结果表明，选择最佳的CpG ODN用于癌症免疫治疗取决于对各种CpG基序的细胞特异性的仔细分析和对负责特定肿瘤中抗肿瘤活性的细胞机制的理解。
Immune stimulatory oligodeoxynucleotides (ODN) with unmethylated CpG motifs are potent inducers of both innate and adaptive immunity. It initially appeared that a single type of optimal CpG motif would work in all applications. We now report that specific motifs of CpG ODN can vary dramatically in their ability to induce individual immune effects and that these differences impact on their antitumor activity in different tumor models. In particular, a distinct type of CpG motif, which has a chimeric backbone in combination with poly(G) tails, is a potent inducer of NK lytic activity but has little effect on cytokine secretion or B cell proliferation. One such NK-optimized CpG ODN (1585) can induce regression of established melanomas in mice. Surprisingly, no such therapeutic effects were seen with CpG ODN optimized for activation of B cells and Th1-like cytokine expression (ODN 1826). The therapeutic effects of CpG 1585 in melanoma required the presence of NK but not T or B cells and were not associated with the induction of a tumor-specific memory response. In contrast, CpG 1826, but not CpG 1585, was effective at inducing regression of the EL4 murine lymphoma; this rejection was associated with the induction of a memory response and although NK cells were necessary, they were not sufficient. These results demonstrate that selection of optimal CpG ODN for cancer immunotherapy depends upon a careful analysis of the cellular specificities of various CpG motifs and an understanding of the cellular mechanisms responsible for the antitumor activity in a particular tumor.