Interferon-γ and tumor necrosis factor-α induce an immunoinhibitory molecule, B7-H1, via nuclear factor-κB activation in blasts in myelodysplastic syndromes
Interferon-γ and tumor necrosis factor-α induce an immunoinhibitory molecule, B7-H1, via nuclear factor-κB activation in blasts in myelodysplastic syndromes
复制标题
DOI：
10.1182/blood-2009-12-255125
复制
发表时间：
2010-08-19
期刊：
影响因子：
20.3
通讯作者：
Ogata, Kiyoyuki
中科院分区：
文献类型：
--
作者：
Kondo, Asaka;Yamashita, Taishi;Ogata, Kiyoyuki
在骨髓增生异常综合征（MDS）的疾病进展过程中，克隆母细胞获得更具侵略性的性质，而非克隆免疫细胞通过未知的机制变得不那么有效。使用MDS细胞系和患者样本，我们发现，免疫抑制分子B7-H1（CD 274）的表达，诱导的干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）对MDS胚细胞。这种诱导与核因子-κ B（NF-κ B）的激活有关，并且几乎完全被NF-κ B抑制剂吡咯烷二硫代氨基甲酸酯（PDTC）阻断。在各种试验中检查时，B7-H1（+）MDS原始细胞的内在增殖能力高于B7-H1（+）MDS原始细胞。此外，B7-H1（+）母细胞抑制T细胞增殖，并诱导T细胞凋亡同种异体共培养。当检查患者的新鲜骨髓样本时，高风险MDS患者的原始细胞表达B7-H1分子的频率高于低风险MDS患者。此外，MDS T细胞通常过表达传递来自B7-H1分子的抑制信号的程序性细胞死亡1（PD-1）分子。总之，这些发现为MDS病理生理学提供了新的见解。IFN γ和TNF α激活NF-κ B，进而诱导MDS母细胞上的B7-H1表达。B7-H1（+）MDS原始细胞具有内在的增殖优势并诱导T细胞抑制，这可能与MDS的疾病进展相关。（血。2010;116（7）：1124-1131）
During disease progression in myelodysplastic syndromes (MDS), clonal blasts gain a more aggressive nature, whereas nonclonal immune cells become less efficient via an unknown mechanism. Using MDS cell lines and patient samples, we showed that the expression of an immunoinhibitory molecule, B7-H1 (CD274), was induced by interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) on MDS blasts. This induction was associated with the activation of nuclear factor-kappa B (NF-kappa B) and nearly completely blocked by an NF-kappa B inhibitor, pyrrolidine dithiocarbamate (PDTC). B7-H1(+) MDS blasts had greater intrinsic proliferative capacity than B7-H1(+) MDS blasts when examined in various assays. Furthermore, B7-H1(+) blasts suppressed T-cell proliferation and induced T-cell apoptosis in allogeneic cocultures. When fresh bone marrow samples from patients were examined, blasts from high-risk MDS patients expressed B7-H1 molecules more often compared with those from low-risk MDS patients. Moreover, MDS T cells often overexpressed programmed cell death 1 (PD-1) molecules that transmit an inhibitory signal from B7-H1 molecules. Taken together, these findings provide new insight into MDS pathophysiology. IFN gamma and TNF alpha activate NF-kappa B that in turn induces B7-H1 expression on MDS blasts. B7-H1(+) MDS blasts have an intrinsic proliferative advantage and induce T-cell suppression, which may be associated with disease progression in MDS. (Blood. 2010;116(7):1124-1131)