Reversal of Immunoparalysis in Humans In Vivo A Double-Blind, Placebo-controlled, Randomized Pilot Study

被引:195
作者
Leentjens, Jenneke [1 ,2 ,5 ]
Kox, Matthijs [1 ,3 ,5 ]
Koch, Rebecca M. [1 ,5 ]
Preijers, Frank [4 ]
Joosten, Leo A. B. [2 ,5 ]
van der Hoeven, Johannes G. [1 ,5 ]
Netea, Mihai G. [2 ,5 ]
Pickkers, Peter [1 ,5 ]
机构
[1] Radboud Univ Nijmegen, Med Ctr, Dept Intens Care Med, Hematol Lab, NL-6500 HB Nijmegen, Netherlands
[2] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Hematol Lab, NL-6500 HB Nijmegen, Netherlands
[3] Radboud Univ Nijmegen, Med Ctr, Dept Anesthesiol, Hematol Lab, NL-6500 HB Nijmegen, Netherlands
[4] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Hematol Lab, NL-6500 HB Nijmegen, Netherlands
[5] Nijmegen Inst Infect Inflammat & Immun N4i, Nijmegen, Netherlands
关键词
lipopolysaccharide; immunoparalysis; IFN-gamma; granulocyte-macrophage; colony-stimulating factor; sepsis; COLONY-STIMULATING FACTOR; ANTIGEN-DR EXPRESSION; TUMOR-NECROSIS-FACTOR; INTERLEUKIN-1 RECEPTOR ANTAGONIST; IFN-GAMMA; INTERFERON-GAMMA; ENDOTOXIN TOLERANCE; WHOLE-BLOOD; ANTIINFLAMMATORY RESPONSE; SEVERE SEPSIS;
D O I
10.1164/rccm.201204-0645OC
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
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.
引用
收藏
页码:838 / 845
页数:8
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