Jenneke Leentjens, Matthijs Kox, Rebecca M. Koch, Frank Preijers, Leo A. B. Joosten, Johannes G. van der Hoeven, Mihai G. Netea and Peter Pickkers  Am. J. Respir. Crit. Care Med. November 1, 2012 vol. 186 no. 9 838-845
Abstract
Rationale: Reversal of sepsis-induced immunoparalysis may reduce the incidence of secondary infections and improve outcome. Although IFN-γ 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-γ 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-γ (100 μg/day; n = 6), GM-CSF (4 μg/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)-α 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-γ group, TNF-α 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-α response during visit 2 was significantly less pronounced in the IFN-γ group (P = 0.01). Moreover, compared with placebo, treatment with IFN-γ increased monocyte HLA-DR expression (P = 0.02). The effects of GM-CSF tended in the same direction as IFN-γ, but were not statistically significant compared with placebo.

Conclusions: IFN-γ partially reverses immunoparalysis in vivo in humans. These results suggest that IFN-γ is a promising treatment option to reverse sepsis-induced immunoparalysis.

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