CD14(+) CD15(-) HLA-DR(-) myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure.
CD14(+) CD15(-) HLA-DR(-) myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure.
复制标题
DOI：
10.1136/gutjnl-2017-314184
复制
发表时间：
2018-06
期刊：
影响因子：
24.5
通讯作者：
Antoniades CG
中科院分区：
文献类型：
--
作者：
Bernsmeier C;Triantafyllou E;Brenig R;Lebosse FJ;Singanayagam A;Patel VC;Pop OT;Khamri W;Nathwani R;Tidswell R;Weston CJ;Adams DH;Thursz MR;Wendon JA;Antoniades CG
慢加急性肝衰竭（ACLF）患者的免疫轻瘫是感染易感性和死亡率增加的原因。免疫抑制性单核CD 14 +HLA-DR−髓源性抑制细胞（M-MDSC）最近被鉴定为抑制免疫介导疾病中的抗菌反应。我们试图描述ACLF患者中M-MDSC的功能和来源，并探索增强抗菌反应的潜在靶点。将ACLF患者（n=41）与健康受试者（n=25）和肝硬化患者（n=22）或急性肝衰竭患者（n=30）进行比较。根据M-MDSC的定义鉴定CD 14 + CD 15-CD 11b +HLA-DR-细胞，并进行详细的免疫表型分析。通过混合淋巴细胞反应评估T细胞活化的抑制。先天免疫功能的评估包括响应于Toll样受体（TLR-2、TLR-4和TLR-9）刺激的细胞因子表达和使用流式细胞术和基于活细胞成像的技术的吞噬测定。ACLF患者的循环CD 14 + CD 15 − CD 11b +HLA-DR− M-MDSC显著扩增（55%的CD 14+细胞）。M-MDSC显示出免疫抑制特性，显著降低T细胞增殖（p=0.01），响应TLR刺激产生较少的肿瘤坏死因子-α/白细胞介素-6（均p<0.01），并减少大肠杆菌的细菌摄取（p<0.001）。HLA-DR在疾病发展过程中持续低表达与继发感染和28天死亡率有关。复发性TLR-2和TLR-4刺激在体外扩增M-MDSC。相比之下，TLR-3激动重建HLA-DR表达和先天免疫功能离体。免疫抑制性CD 14 +HLA-DR− M-MDSC在ACLF患者中扩增。它们通过抑制T细胞功能，减弱抗微生物天然免疫应答，与继发感染，疾病严重程度和预后相关。TLR-3激动逆转了M-MDSC扩增和先天免疫功能，值得进一步评估作为潜在的免疫抑制剂。
Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR− myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15−CD11b+HLA-DR− cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. Circulating CD14+CD15−CD11b+HLA-DR− M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. Immunosuppressive CD14+HLA-DR− M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.
登录
查看更多内容
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
DOI：
10.4049/jimmunol.1000901
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lechner MG;Liebertz DJ;Epstein AL
通讯作者：
Epstein AL
影响因子：
5.5
作者：
Bunt, Stephanie K.;Clements, Virginia K.;Ostrand-Rosenberg, Suzanne
通讯作者：
Ostrand-Rosenberg, Suzanne
DOI：
10.1093/jnci/djs436
发表时间：
2012-12-05
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Chew V;Tow C;Huang C;Bard-Chapeau E;Copeland NG;Jenkins NA;Weber A;Lim KH;Toh HC;Heikenwalder M;Ng IO;Nardin A;Abastado JP
通讯作者：
Abastado JP
影响因子：
16.6
作者：
Bronte V;Brandau S;Chen SH;Colombo MP;Frey AB;Greten TF;Mandruzzato S;Murray PJ;Ochoa A;Ostrand-Rosenberg S;Rodriguez PC;Sica A;Umansky V;Vonderheide RH;Gabrilovich DI
通讯作者：
Gabrilovich DI