Reversal of Immunoparalysis in Humans In Vivo A Double-Blind, Placebo-controlled, Randomized Pilot Study
Reversal of Immunoparalysis in Humans In Vivo A Double-Blind, Placebo-controlled, Randomized Pilot Study
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DOI：
10.1164/rccm.201204-0645oc
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发表时间：
2012-11-01
影响因子：
24.7
通讯作者：
Pickkers, Peter
中科院分区：
文献类型：
--
作者：
Leentjens, Jenneke;Kox, Matthijs;Pickkers, Peter
原理：恢复脓毒症诱导的免疫麻痹可降低继发感染的发生率并改善结局。尽管IFN-γ和粒细胞-巨噬细胞集落刺激因子（GM-CSF）恢复了脓毒症患者的离体刺激的白细胞的免疫能力，但对体内免疫麻痹的影响尚不清楚。我们在18名接受大肠杆菌内毒素治疗的健康男性志愿者中进行了一项双盲、安慰剂对照、随机研究（LPS; 2 ng/kg，静脉内）。在第2、4和6天，受试者接受IFN-γ皮下注射，（100 μ g/天; n = 6），GM-CSF（4 μ g/kg/天; n = 6）或安慰剂（NaCl 0.9%; n = 6）。测量和主要结果：在安慰剂组，免疫麻痹表现为访视2期间LPS诱导的肿瘤坏死因子（TNF）-α血浆浓度降低60%（48-71%）（P = 0.03），而IL-10应答没有显著减弱（39% [2-65%]; P = 0.15）。相比之下，在IFN-γ组中，第2次访视期间TNF-α浓度未显著降低（28% [1-47%]; P = 0.09），而IL-10应答显著降低（降低54% [47-66%]; P = 0.03）。与安慰剂组相比，IFN-γ组访视2期间LPS诱导的TNF-α反应的降低显著较不明显（P = 0.01）。此外，与安慰剂相比，IFN-γ治疗增加单核细胞HLA-DR表达（P = 0.02）。GM-CSF的影响倾向于在相同的方向，IFN-γ，但没有统计学意义上与placebo.Conclusions相比：IFN-γ部分逆转免疫麻痹在人体内。这些结果表明，IFN-γ是一种有前途的治疗选择，以扭转败血症诱导的免疫麻痹。
Rationale: Reversal of sepsis-induced immunoparalysis may reduce the incidence of secondary infections and improve outcome. Although IFN-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) restore immune competence of ex vivo stimulated leukocytes of patients with sepsis, effects on immunoparalysis in vivo are not known.Objectives: To investigate the effects of IFN-gamma and GM-CSF on immunoparalysis in vivo in humans.Methods: We performed a double-blind, placebo-controlled, randomized study in 18 healthy male volunteers that received Escherichia coli endotoxin (LPS; 2 ng/kg, intravenously) on days 1 and 7 (visits 1 and 2). On days 2, 4, and 6, subjects received subcutaneous injections of IFN-gamma (100 mu g/day; n = 6), GM-CSF (4 mu g/kg/day; n = 6), or placebo (NaCl 0.9%; n = 6).Measurements and Main Results: In the placebo group, immunoparalysis was illustrated by a 60% (48-71%) reduction of LPS-induced tumor necrosis factor (TNF)-alpha plasma concentrations during visit 2 (P = 0.03), whereas the antiinflammatory IL-10 response was not significantly attenuated (39% [2-65%]; P = 0.15). In contrast, in the IFN-gamma group, TNF-alpha concentrations during visit 2 were not significantly attenuated (28% [1-47%]; P = 0.09), whereas the IL-10 response was significantly lower (reduction of 54% [47-66%]; P = 0.03). Compared with the placebo group, the reduction in the LPS-induced TNF-alpha response during visit 2 was significantly less pronounced in the IFN-gamma group (P = 0.01). Moreover, compared with placebo, treatment with IFN-gamma increased monocyte HLA-DR expression (P = 0.02). The effects of GM-CSF tended in the same direction as IFN-gamma, but were not statistically significant compared with placebo.Conclusions: IFN-gamma partially reverses immunoparalysis in vivo in humans. These results suggest that IFN-gamma is a promising treatment option to reverse sepsis-induced immunoparalysis.