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Monocyte deactivation in septic patients: Restoration by IFN-γ treatment

Nature Medicine volume 3, pages 678–681 (1997)Cite this article

Abstract

Neutralization of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin-1 (IL-1), decreases mortality in several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to animals, which succumb to shock during the first 72 hours, we found that many patients die much later with signs of opportunistic infections accompanied by downregulation of their monocytic HLA-DR expression and reduced ability to produce lipopolysaccharide (LPS)-induced TNF-α in vitro1–3. This phenomenon of monocyte deactivation in septic patients with fatal outcome shows similarities to experimental monocytic refractoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-β (TGF-β)4. In order to strengthen their antimicrobial defense, here we tested whether interferon-γ (IFN-γ) can improve monocytic functions in these patients and in experimental monocytic deactivation. The considerably lowered in vitro levels of LPS-induced TNF-α in these situations were significantly enhanced by IFN-γ, but did not reach the extremely high levels of IFN-γ primed naive cells from healthy donors. Moreover, IFN-γ applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-α secretion. Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients. These data suggest that IFN-γ treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.

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Affiliations

  1. Institute of Medical Immunology,Humboldt-University Berlin, Medical School (Charité), D-13353, Berlin, Germany

    Wolf-Dietrich Döcke, Felix Randow, Uta Syrbe, Khusru Asadullah & Hans-Dieter Volk

  2. Clinic of Anesthesiology and Intensive Care Medicine, Humboldt-University Berlin, Medical School (Charité), D-10098, Berlin, Germany

    Dietmar Krausch & Wolfgang Kox

  3. Department of Nephrology and Internal Intensive Care, Humboldt-University Berlin, Virchow Clinic, D-13353, Berlin, Germany

    Petre Reinke

  4. Clinic of Dermatology, Humboldt-University Berlin, Medical School (Charité), D-10098, Berlin, Germany

    Khusru Asadullah

Authors
  1. Wolf-Dietrich Döcke
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  2. Felix Randow
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  3. Uta Syrbe
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  4. Dietmar Krausch
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  5. Khusru Asadullah
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  6. Petre Reinke
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  7. Hans-Dieter Volk
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  8. Wolfgang Kox
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Döcke, WD., Randow, F., Syrbe, U. et al. Monocyte deactivation in septic patients: Restoration by IFN-γ treatment. Nat Med 3, 678–681 (1997). https://doi.org/10.1038/nm0697-678

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