Anti-PD-L1 peptide improves survival in sepsis.
Anti-PD-L1 peptide improves survival in sepsis.
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DOI：
10.1016/j.jss.2016.08.099
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Hotchkiss RS
中科院分区：
文献类型：
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作者：
Shindo Y;McDonough JS;Chang KC;Ramachandra M;Sasikumar PG;Hotchkiss RS
脓毒症仍然是大多数icu患者死亡的主要原因。脓毒症的许多死亡是由于进入免疫抑制期的患者的医院感染。脓毒症中免疫抑制的一个原因是程序性细胞死亡-1 （PD-1）与其配体（PD-L1）相互作用介导的t细胞衰竭。研究表明，阻断PD-1与PD-L1与敲除小鼠或抑制性抗体的相互作用，可逆转T细胞功能障碍，提高败血症存活率。本研究评估了一种新型短效肽（化合物8）在临床相关的二次命中真菌脓毒症模型中抑制PD-1/PD-L1信号传导的功效。小鼠进行盲肠结扎和穿刺诱导腹膜炎。三天后，小鼠静脉注射白色念珠菌。在感染念珠菌48小时后，用化合物8或无活性肽治疗小鼠。流式细胞术检测念珠菌感染对CD4+、CD8+、自然杀伤细胞（NK）和NKT细胞PD-1和PD-L1共抑制分子表达的影响。我们还考察了化合物8对存活的影响。真菌感染4天后，脓毒症小鼠与假手术小鼠相比，CD4+、NK和NKT细胞上PD-1和/或PD-L1的表达明显增加（CD4+上PD-1百分比，11.9%比2.8%；NKT上PD-L1百分比，14.8%比0.5%）。与对照组相比，化合物8使生存率提高了2倍，从30%提高到60%，p < 0.05。化合物8可显著提高脓毒症临床相关免疫抑制模型的生存率。这些结果支持针对这种致命疾病的t细胞衰竭的免疫辅助治疗。
Sepsis remains a leading cause of death in most ICUs. Many deaths in sepsis are due to nosocomial infections in patients who have entered the immunosuppressive phase of the disorder. One cause of immunosuppression in sepsis is T-cell exhaustion mediated by programmed cell death-1 (PD-1) interaction with its ligand (PD-L1). Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T cell dysfunction and improved sepsis survival. This study assessed the efficacy of a novel short-acting peptide (Compound 8) that inhibits PD-1/PD-L1 signaling in a clinically-relevant second-hit fungal sepsis model. Mice underwent cecal ligation and puncture to induce peritonitis. Three days later, mice received intravenous injection of Candida albicans. Forty-eight hours following Candida infection, mice were treated with Compound 8 or inactive peptide. The effect of Candida infection on expression of co-inhibitory molecules, PD-1 and PD-L1 were quantitated by flow cytometry on CD4+, CD8+, natural killer (NK) cells, and NKT cells. The effect of Compound 8 on survival was also examined. Four days after fungal infection, PD-1 and/or PD-L1 expressions were markedly increased on CD4+, NK, and NKT cells in septic versus sham-operated mice (%PD-1 on CD4+, 11.9% vs 2.8%; and %PD-L1 on NKT, 14.8% vs 0.5%). Compared to control, Compound 8 caused a two-fold increase in survival from 30% to 60%, p < 0.05. Compound 8 significantly improved survival in a clinically-relevant immunosuppressive model of sepsis. These results support immuno-adjuvant therapy targeting T-cell exhaustion in this lethal disease.
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幸存的败血症运动：严重败血症和化粪池冲击管理的国际指南，2012年。
影响因子：
38.9
作者：
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通讯作者：
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影响因子：
4.4
作者：
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通讯作者：
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发表时间：
2014-02-01
期刊：
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影响因子：
--
作者：
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通讯作者：
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影响因子：
120.7
作者：
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DOI：
10.1038/nri3552
发表时间：
2013-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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