Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis.
Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis.
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DOI：
10.1186/cc12711
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发表时间：
2013-05-11
期刊：
影响因子：
--
通讯作者：
Hotchkiss RS
中科院分区：
文献类型：
--
作者：
Chang KC;Burnham CA;Compton SM;Rasche DP;Mazuski RJ;McDonough JS;Unsinger J;Korman AJ;Green JM;Hotchkiss RS
真菌败血症是重症监护病房患者中日益常见的问题。尽管抗菌治疗对大多数真菌病原体具有高度活性，但真菌败血症的死亡率仍然很高，这一发现与许多播散性真菌病患者存在的宿主免疫缺陷一致。最近发现的一种免疫学缺陷是败血症患者由于程序性细胞死亡-1(PD-1)表达增加而导致的T细胞“衰竭”。本研究在两种真菌败血症小鼠模型上测试了抗PD-1和抗PD-L1(抗PD-L1)拮抗抗体提高存活率和逆转败血症诱导的免疫抑制的能力。采用两种不同的感染模型，即原发真菌败血症和盲肠亚致死性结扎穿孔(CLP)后继发真菌败血症，在感染后24~48h分别给予抗PD-1和抗PD-L1，观察其对小鼠存活时间、干扰素-γ产生和MHC II表达的影响。抗PD-1和抗PD-L1抗体在提高原发和继发霉菌败血症的存活率方面非常有效。这两种抗体都能逆转败血症诱导的干扰素伽马的抑制和抗原提呈细胞上MHC II的表达增加。阻断细胞毒性T淋巴细胞抗原-4(CTLA-4)也可以提高真菌败血症的存活率。CTLA-4是一种在脓毒症中上调的第二种负向共刺激分子，其作用类似PD-1，以抑制T细胞功能。用抗PD-1、抗PD-L1和抗CTLA-4抗体进行免疫辅助治疗可逆转脓毒症引起的免疫抑制，提高真菌败血症患者的存活率。本研究结果与以往研究结果一致，表明阻断PD-1和CTLA-4可提高细菌败血症患者的存活率。因此，免疫佐剂治疗代表了一种新的治疗败血症的方法，并可能在疾病中具有广泛的适用性。鉴于迄今为止抗PD-1抗体在癌症临床试验中的相对安全性，应积极考虑对免疫抑制的危及生命的脓毒症患者进行抗PD-1治疗。
Fungal sepsis is an increasingly common problem in intensive care unit patients.Mortality from fungal sepsis remains high despite antimicrobial therapy that is highly active against most fungal pathogens, a finding consistent with defective host immunity that is present in many patients with disseminated fungemia.One recently recognized immunologic defect that occurs in patients with sepsis is T cell "exhaustion" due to increased expression of programmed cell death -1 (PD-1).This study tested the ability of anti-PD-1 and anti-programmed cell death ligand -1 (anti-PD-L1) antagonistic antibodies to improve survival and reverse sepsis-induced immunosuppression in two mouse models of fungal sepsis. Fungal sepsis was induced in mice using two different models of infection, that is, primary fungal sepsis and secondary fungal sepsis occurring after sub-lethal cecal ligation and puncture (CLP).Anti-PD-1 and anti-PD-L1 were administered 24 to 48 h after fungal infection and effects on survival, interferon gamma production, and MHC II expression were examined. Anti-PD-1 and anti-PD-L1 antibodies were highly effective at improving survival in primary and secondary fungal sepsis.Both antibodies reversed sepsis-induced suppression of interferon gamma and increased expression of MHC II on antigen presenting cells.Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a second negative co-stimulatory molecule that is up-regulated in sepsis and acts like PD-1 to suppress T cell function, also improved survival in fungal sepsis. Immuno-adjuvant therapy with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies reverse sepsis-induced immunosuppression and improve survival in fungal sepsis.The present results are consistent with previous studies showing that blockade of PD-1 and CTLA-4 improves survival in bacterial sepsis.Thus, immuno-adjuvant therapy represents a novel approach to sepsis and may have broad applicability in the disorder.Given the relative safety of anti-PD-1 antibody in cancer clinical trials to date, therapy with anti-PD-1 in patients with life-threatening sepsis who have demonstrable immunosuppression should be strongly considered.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
7
作者：
Brown KE;Freeman GJ;Wherry EJ;Sharpe AH
通讯作者：
Sharpe AH
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