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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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References

  1. Volk, H.D. et al. Diagnostic value of an immune monitoring program for the clinical management of immunosuppressed patients with septic complications. Clin. Transplant 3. 246–252 (1989).

    Google Scholar 

  2. Volk, H.D. et al. Alterations in function and phenotype of monocytes from patients with septic disease: Predictive value and new therapeutic strategies. in Host Defense Dysfunction in Trauma, Shock and Sepsis. (eds. Faist, E. and Meakins, J.L.) 246–271 (Springer-Verlag, Berlin-Heidelberg-New York, 1993).

    Google Scholar 

  3. Döcke, W.D. et al. Monocytic deactivation in fatal septic disease — Role of tumor necrosis factor-α and interleukin-10. in The Immune Consequences of Trauma, Shock and Sepsis — Mechanisms and Therapeutic Approaches. Vol.1, MOF, MODS and SIRS: Basic Mechanisms in Inflammation and Tissue Injury, (eds. Faist, E., Baue, A.E. & Schildberg, F.W.) 162–168 (Pabst Science Publishers, Lengerich, Germany, 1996).

    Google Scholar 

  4. Randow, F. Mechanism of endotoxin desensitization: Involvement of interleukin 10 and transforming growth factor beta. J. Exp. Med. 181, 1887–1892 (1995).

    Article  CAS  Google Scholar 

  5. Beutler, B., Milsark, I.W. & Cerami, A.C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229, 869–871 (1985).

    Article  CAS  Google Scholar 

  6. Natanson, C., Hoffman, W.D., Suffredini, A.F., Eichacker, P.Q. & Danner, R.L. Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann. Intern. Med. 120, 771–783 (1994).

    Article  CAS  Google Scholar 

  7. Fisher, C.J. et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome: Results from a randomized, double-blind, placebo-controlled trial. JAMA 271, 1836–1843 (1994).

    Article  Google Scholar 

  8. Fisher, C.J. et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. N. Engl. J. Med. 334, 1697–1702 (1996).

    Article  CAS  Google Scholar 

  9. Echtenacher, B., Falk, W., Mannel, D.N. & Krammer, P.H. Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J. Immunol. 145, 3762–3766 (1990).

    CAS  PubMed  Google Scholar 

  10. Pfeffer, K. et al. Mice deficient for the 55 kD tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73, 457–467 (1993).

    Article  CAS  Google Scholar 

  11. Platzer, C., Meisel, C., Vogt, K., Platzer, M. & Volk, H.D. Up-regulation of mono-cytic IL-10 by tumor necrosis factor-alpha and cAMP elevating drugs. Int. Immunol. 7, 517–523 (1995).

    Article  CAS  Google Scholar 

  12. Bone, R.C. Sir Isaac Newton, sepsis, and CARS. Crit. Care Med. 24, 1125–1128 (1996).

    Article  CAS  Google Scholar 

  13. Munoz, C. et al. Dysregulation of in vitro cytokine production by monocytes during sepsis. J. Clin. Invest. 88, 1747–1754 (1991).

    Article  CAS  Google Scholar 

  14. Faist, E. et al. Immunomodulatory therapy with thymopentin and indomethacin: Successful restoration of interleukin-2 synthesis in patients undergoing major surgery. Ann. Surg. 214, 264–273 (1991).

    Article  CAS  Google Scholar 

  15. Young, H.A. & Hardy K.J. Role of interferon-gamma in immune cell regulation. J.Leukocyt. Biol. 58, 373–381 (1995).

    Article  CAS  Google Scholar 

  16. Hart, P.H., Whitty G.A., Piccoli, D.S. & Hamilton, J.A. Control by IFN-gamma and PGE2 of TNF-alpha and IL-1 production by human monocytes. Immunology 66, 376–383 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Donnelly, R.P., Freeman, S.L. & Hayes, M.P. Inhibition of IL-10 expression by IFN-gamma up-regulates transcription of TNF-alpha in human monocytes. J. Immunol. 155, 1420–1427 (1995).

    CAS  PubMed  Google Scholar 

  18. Heinzel, F.P. The role of IFN-gamma in the pathology of experimental endotoxemia. J. Immunol. 145, 2920–2924 (1990).

    CAS  PubMed  Google Scholar 

  19. Bone, R.C. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee, American College of Chest Physicians/Society of Critical Care Medicine. Chest 101, 1644–1655 (1992).

    Article  CAS  Google Scholar 

  20. Kaul, M., Eiselstein, J., Kempeni, J. & Daum, L. TNF-neutralization in sepsis guided by IL-6 serum levels. Sixth International TNF Congress, Rhodes, Hellas, Greece, 8–12 May 1996. [Abstr.] Eur. Cytokine Netw. 7, 283 (1996).

    Google Scholar 

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Authors and 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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  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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