Cytokine Neutralization: An Overview

  • E. Abraham
Part of the Update in Intensive Care Medicine book series (volume 31)

Abstract

An excessive inflammatory response accompanies the initial stages of severe infection and appears to contribute to organ system failure and death in this setting [1, 2, 3]. A number of immunomodulatory therapies aimed at decreasing the dysregulated inflammatory response have been examined in patients with sepsis (Table 1). Despite initially encouraging results with many of these approaches in Phase II clinical trials, larger Phase III studies have not demonstrated benefit. In contrast to the lack of effect of immunomodulatory agents in sepsis, therapies directed against specific pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α or interleukin (IL)-1,have produced remarkable clinical response in diseases such as rheumatoid arthritis and Crohn’s disease [4, 5, 6].
Table 1.

Some immunomodulatory therapies examined in sepsis

Keywords

Placebo Arthritis Europe Corticosteroid Pneumonia 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Abraham E (1997) Therapies for sepsis. Emerging therapies for sepsis and septic shock. West J Med 166:195–200PubMedGoogle Scholar
  2. 2.
    Parrillo JE, Parker MM, Natanson C, et al (1990) Septic shock in humans. Ann Intern Med 113:227–242PubMedGoogle Scholar
  3. 3.
    Zeni F, Freeman B, Natanson C (1997) Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 25:1095–1100PubMedCrossRefGoogle Scholar
  4. 4.
    Targan SR, Hanauer SB, van Deventer S J, et al (1997) A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. New Engl J Med 337:1029–1035PubMedCrossRefGoogle Scholar
  5. 5.
    Lorenz HM, Antoni C, Valerius T, et al (1996) In vivo blockade of TNF-alpha by intravenous infusion of a chimeric monoclonal TNF-alpha antibody in patients with rheumatoid arthritis. Short term cellular and molecular effects. J Immunol 156:1646–1653PubMedGoogle Scholar
  6. 6.
    Elliott MJ, Maini RN, Feldmann M, et al (1994) Repeated therapy with monoclonal antibody to tumor necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 344:1125–1127PubMedCrossRefGoogle Scholar
  7. 7.
    Bone RC, Balk RA, Cerra FB, et al (1992) ACCP/SCCM consensus conference: Definitions for sepsis and organ failure and guidehnes for the use of innovative therapies in sepsis. Chest 101:1644–1655PubMedCrossRefGoogle Scholar
  8. 8.
    Bone RC, Fisher Jr. CJ, Clemmer TP, et al (1989) Sepsis syndrome: A valid clinical entity Crit Care Med 17:389–393PubMedCrossRefGoogle Scholar
  9. 9.
    Abraham E, Wunderink R, Silverman H, et al (1995) Monoclonal antibody to human tumor necrosis factor alpha (TNF MAb): Efficacy and safety in patients with the sepsis syndrome. JAMA 273:934–941PubMedCrossRefGoogle Scholar
  10. 10.
    Cohen J, Carlet J (1996) INTERSEPT: An international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-α in patients with sepsis. Crit Care Med 24:1431–1440PubMedCrossRefGoogle Scholar
  11. 11.
    Abraham E, Glauser MP, Butler T, et al (1997) p55 tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. JAMA 277:1531–1534PubMedCrossRefGoogle Scholar
  12. 12.
    Opal SM, Fisher CJ, Pribble JP, et al (1997) The confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med 25:1115–1124PubMedCrossRefGoogle Scholar
  13. 13.
    Abraham E, Anzueto A, Gutierrez G, et al (1998) Monoclonal antibody to human tumor necrosis factor alpha (TNF Mab) in the treatment of patients with septic shock: A multi-center, placebo controlled, randomized, double-blind clinical trial. Lancet 351:929–933PubMedGoogle Scholar
  14. 14.
    Zanetti G, Heumann D, Gerain J, et al (1992) Cytokine production after intravenous or peritoneal gram-negative bacterial challenge in mice. J Immunol 148:1890–1897PubMedGoogle Scholar
  15. 15.
    Fisher CJ Jr., Agosti JM, Opal SM, et al (1996) Treatment of septic shock with the tumor necrosis factor receptor Fc fusion protein. N Engl J Med 334:1697–1702PubMedCrossRefGoogle Scholar
  16. 16.
    Sprung CL, Finch RG, Thijs LG, Glauser MP (1996) International sepsis trial (INTERSEPT): role and impact of a clinical evaluation committee. Crit Care Med 24:1441–1447PubMedCrossRefGoogle Scholar
  17. 17.
    Ohlsson K, Bjork P, Bergenfeldt M, Hageman R, Thompson RC (1990) Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 348:550–552PubMedCrossRefGoogle Scholar
  18. 18.
    Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA (1991) A specific receptor antagonist for interleukin-1 prevents Escherichia coli-induced shock. FASEB J 5:338–343PubMedGoogle Scholar
  19. 19.
    Hawes AS, Fischer E, Marano MA, et al (1993) Comparison of peripheral blood leukocyte kinetics after live Escherichia coli, endotoxin, or interleukin-1 alpha administration. Studies using a novel interleukin-1 receptor antagonist. Ann Surg 218:79–90PubMedCrossRefGoogle Scholar
  20. 20.
    Fischer E, Marano MA, Van Zee KJ, et al (1992) Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. J Clin Invest 89:1551–1557PubMedCrossRefGoogle Scholar
  21. 21.
    Fisher CJ Jr., Slotman GJ, Opal SM, et al (1994) Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. The IL-1RA Sepsis Syndrome Study Group. Crit Care Med 22:12–21PubMedGoogle Scholar
  22. 22.
    Fisher CJ Jr, Dhainaut JF, Opal SM, et al (1994) Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-bUnd, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 271:1836–1843PubMedCrossRefGoogle Scholar
  23. 23.
    Tracey KJ, Fong Y, Hesse DG, et al (1987) Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 330:662–664PubMedCrossRefGoogle Scholar
  24. 24.
    Fong Y, Tracey KJ, Moldawer LL, et al (1989) Antibodies to cachectin/TNF reduce interleukin-1 and interleukin-6 appearance during lethal bacteremia. J Exp Med 170:1627–1633PubMedCrossRefGoogle Scholar
  25. 25.
    Hinshaw LB, Tekamp-Olson P, Chang AC, et al (1990) Survival of primates in LDioo septic shock following therapy with antibody to tumor necrosis factor (TNF). Cire Shock 30:279–292Google Scholar
  26. 26.
    Van Zee KJ, Moldawer LL, Oldenburg HAS, et al (1996) Protection against lethal Escherichia coli bacteremia in baboons (Papio anubis) by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion protein, Ro 45-2081. J Immunol 156:2221–2230PubMedGoogle Scholar
  27. 27.
    Hinshaw LB, Emerson TE Jr., Taylor FB Jr., et al (1992) Lethal S. aureus shock in primates: prevention of death with anti-TNF antibody J Trauma 33:568–573PubMedCrossRefGoogle Scholar
  28. 28.
    Vincent JL, Bakker J, Marecaux G, Schandene L, Kahn RJ, Dupont E ( 1992) Administration of anti-TNF antibody improves left ventricular function in septic shock patients. Results of a pilot study Chest 101:810–815PubMedCrossRefGoogle Scholar
  29. 29.
    Dhainaut JF, Vincent JL, Richard C, et al (1995) CDP571, a humanized antibody to human tumor necrosis factor-α: Safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. Crit Care Med 23:1461–1469PubMedCrossRefGoogle Scholar
  30. 30.
    Reinhart K, Wiegand-Lohnert C, Grimminger F, et al (1996) Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: A multicenter, randomized, placebo-controlled, dose-ranging study Crit Care Med 24:733–742PubMedCrossRefGoogle Scholar
  31. 31.
    Giroir BP, Quint PA, Barton P, et al (1997) Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis. Lancet 350:1439–1443PubMedCrossRefGoogle Scholar
  32. 32.
    Bone RC (1994) Gram-positive organisms and sepsis. Arch Intern Med 154:26–34PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • E. Abraham
    • 1
  1. 1.Division of Pulmonary Sciences and Critical Care MedicineUniversity of Colorado Health Sciences CenterDenverUSA

Personalised recommendations