Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis.
Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis.
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DOI：
10.1186/cc13176
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发表时间：
2014-01-04
期刊：
影响因子：
--
通讯作者：
Hotchkiss R
中科院分区：
文献类型：
--
作者：
Chang K;Svabek C;Vazquez-Guillamet C;Sato B;Rasche D;Wilson S;Robbins P;Ulbrandt N;Suzich J;Green J;Patera AC;Blair W;Krishnan S;Hotchkiss R
脓毒症的一个主要病理生理机制是宿主免疫力受损，导致无法根除入侵病原体并增加继发感染的易感性。尽管存在许多免疫抑制机制，但抑制性受体程序性细胞死亡 1 (PD-1) 及其配体 (PD-L1) 的表达增加被认为发挥着关键作用。新认识到的 T 细胞耗竭现象部分是由 PD-1 对 T 细胞的影响介导的。本研究测试了抗 PD-1 和抗 PD-L1 抗体预防脓毒症患者细胞凋亡和改善淋巴细胞功能的能力。血液采集自 43 名脓毒症患者和 15 名非脓毒症危重患者。通过流式细胞术定量抗 PD-1、抗 PD-L1 或同种型对照抗体对淋巴细胞凋亡以及干扰素 γ (IFN-γ) 和白细胞介素 2 (IL-2) 产生的影响。与非脓毒症患者相比，脓毒症患者淋巴细胞产生的 IFN-γ 和 IL-2 减少，CD8 T 细胞 PD-1 表达增加，PD-L1 表达减少（P<0.05）。与非脓毒症患者相比，脓毒症患者的单核细胞 PD-L1 表达增加，HLA-DR 表达减少（P<0.01）。在 ICU 中，随着 PD-L1、IFN-γ 和 IL2 的减少，PD-1 的 CD8 T 细胞表达随着时间的推移而增加。此外，CD8 PD-1 表达最高且 CD8 PD-L1 表达最低的供体单核细胞中 HLA-DR 表达水平也较低，继发感染率增加，表明免疫衰竭表型更为严重。用抗 PD-1 或抗 PD-L1 抗体治疗脓毒症患者的细胞可减少脓毒症患者的细胞凋亡并增加 IFN-γ 和 IL-2 的产生； (P<0.01)。 PD-1阳性CD4 T细胞百分比与细胞凋亡程度相关（P<0.01）。体外阻断 PD-1:PD-L1 通路可减少脓毒症患者的细胞凋亡并改善免疫细胞功能。目前的结果，加上细菌和真菌感染动物模型中抗 PD-1 和抗 PD-L1 的多项积极研究，以及迄今为止人类肿瘤学试验中抗 PD-1/抗 PD-L1 的相对安全性，有力地支持了在败血症（一种高死亡率疾病）中测试这些抗体的临床试验的启动。
A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients. Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production were quantitated by flow cytometry. Lymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01). In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.
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DOI：
10.1186/cc10112
发表时间：
2011
期刊：
Critical care (London, England)
影响因子：
--
作者：
Guignant C;Lepape A;Huang X;Kherouf H;Denis L;Poitevin F;Malcus C;Chéron A;Allaouchiche B;Gueyffier F;Ayala A;Monneret G;Venet F
通讯作者：
Venet F
影响因子：
120.7
作者：
Boomer, Jonathan S.;To, Kathleen;Chang, Kathy C.;Takasu, Osamu;Osborne, Dale F.;Walton, Andrew H.;Bricker, Traci L.;Jarman, Stephen D., II;Kreisel, Daniel;Krupnick, Alexander S.;Srivastava, Anil;Swanson, Paul E.;Green, Jonathan M.;Hotchkiss, Richard S.
通讯作者：
Hotchkiss, Richard S.
DOI：
10.1073/pnas.0809422106
发表时间：
2009-04-14
影响因子：
11.1
作者：
Huang, Xin;Venet, Fabienne;Ayala, Alfred
通讯作者：
Ayala, Alfred
影响因子：
8.8
作者：
Levy, MM;Fink, MP;Ramsay, G
通讯作者：
Ramsay, G
DOI：
10.1186/cc12711
发表时间：
2013-05-11
期刊：
Critical care (London, England)
影响因子：
--
作者：
Chang KC;Burnham CA;Compton SM;Rasche DP;Mazuski RJ;McDonough JS;Unsinger J;Korman AJ;Green JM;Hotchkiss RS
通讯作者：
Hotchkiss RS