Cytosine-phosphorothionate- guanine oligodeoxynucleotides exacerbates hemophagocytosis by inducing tumor necrosis factor-α production in mice after bone marrow transplanation.
Cytosine-phosphorothionate- guanine oligodeoxynucleotides exacerbates hemophagocytosis by inducing tumor necrosis factor-α production in mice after bone marrow transplanation.
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胞嘧啶-硫代磷酸-鸟嘌呤寡脱氧核苷酸通过诱导骨髓移植后小鼠肿瘤坏死因子-α 的产生来恶化噬血细胞作用。
DOI：
10.1016/j.bbmt.2015.12.018
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
and Sawada K.
中科院分区：
文献类型：
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作者：
Liu J;Guo YM;Onai N;Ohyagi H; Hirokawa M;Takahashi N;Tagawa H;Ubukawa K;Kobayahi I;Tezuka H;Minamiya Y;Ohteki T;and Sawada K.
噬血细胞综合征 (HPS) 通常与造血干细胞移植相关，TNF-α 抑制剂对治疗有一定疗效。然而，HPS 发生的机制以及 TNF-α 抑制剂如何对 HPS 管理发挥一定作用仍不清楚。我们评估了 Toll 样受体 (TLR) 配体，尤其是胞嘧啶-硫代磷酸-鸟嘌呤寡脱氧核苷酸 (CpG)（一种 TLR9 配体）对接受同种或同种异体骨髓 (BM) 细胞（Syn-BMT、Allo-BMT）或同种异体 BM 细胞加脾细胞移植以促进移植物抗宿主病（GVHD 小鼠）的小鼠的 HPS 的影响。噬血细胞现象是 BMT 早期的一个常见特征，但在 Syn-BMT 和 Allo-BMT 小鼠中，噬血细胞现象消退。然而，在 GVHD 小鼠中，噬血作用持续存在，并伴随着 IFN-γ（而非 TNF-α）产生的上调，并且通过阻断 IFN-γ（而非 TNF-α）来抑制噬血作用。单次注射 TLR9 配体 CpG 会促进所有 BMT 小鼠的 HPS，并导致 GVHD 小鼠死亡，同时伴随着 TNF-α、IL-6 和 IFN-γ 的产生大幅上调。阻断 TNF-α（而非 IL-6 或 IFN-γ）可抑制所有 BMT 小鼠中 CpG 诱导的 HPS，并使 GVHD 小鼠免于 CpG 诱导的死亡。因此，TLR9 信号传导介导 BMT 小鼠中 TNF-α 驱动的 HPS，并通过 TNF-α 抑制得到有效治疗。
Hemophagocytic syndrome (HPS) is frequently associated with hematopoietic stem cell transplantation and is treated with some benefit derived from TNF-α inhibitors. However, the mechanisms of how HPS occurs and how a TNF-α inhibitor exerts some benefit to HPS management have remained unclear. We evaluated the effect of toll-like receptor (TLR) ligands, especially focusing on cytosine-phosphorothionate-guanine oligodeoxynucleotide (CpG), a TLR9 ligand, on HPS in mice that underwent transplantation with syngeneic or allogeneic bone marrow (BM) cells (Syn-BMT, Allo-BMT), or with allogeneic BM cells plus splenocytes to promote graft-versus-host disease (GVHD mice). Hemophagocytosis was a common feature early after all BMT, but it subsided in Syn-BMT and Allo-BMT mice. In GVHD mice, however, hemophagocytosis persisted and was accompanied by upregulated production of IFN-γ but not TNF-α, and it was suppressed by blockade of IFN-γ but not TNF-α. A single injection of the TLR9 ligand CpG promoted HPS in all BMT mice and was lethal in GVHD mice, accompanied by greatly upregulated production of TNF-α, IL-6, and IFN-γ. Blocking of TNF-α, but not IL-6 or IFN-γ, suppressed CpG-induced HPS in all BMT mice and rescued GVHD mice from CpG-induced mortality. Thus, TLR9 signaling mediates TNF-α–driven HPS in BMT mice and is effectively treated through TNF-α inhibition.