Receptor Blocking Agents: Why Did They Fail?

  • G. Berlot
  • M. Soiat
Conference paper


The wide array of cardiorespiratory and metabolic derangements commonly observed in sepsis is caused by the production and the release by the immunocompetent and the endothelial cells of a number of mediators deriving from the interaction between the infecting agent and the host [1], including the tumour necrosis factor (TNF), the platelet activating factor (PAF), an ever-increasing number of Interleukins (IL), the endothelin, the arachidonic acid derivates and many others. The same substances are also implicated in the development of the Systemic Inflammatory Response Syndrome (SIRS), which, however, is primed by non-infectious stimuli, such as acute pancreatitis, ruptured aortic aneurysms etc. [21. Similarly to other biological systems (e.g. the coagulative cascade), the secretion of many if not all of these mediators is accompanied by the simultaneous release of substances with inhibitory properties, theleologically aimed to down-regulate the inflammatory process. Basically, these agents act by binding and inactivating the circulating septic mediators and/or by occupying their receptors on the surface of the target cells, thus making them unavailable for the active mediators [3].


Septic Shock Systemic Inflammatory Response Syndrome Septic Patient Soluble Receptor Sepsis Syndrome 


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  1. 1.
    Rackow EC, Astiz ME (1991) Pathophysiology and treatment of septic shock. JAMA 266: 548–554PubMedCrossRefGoogle Scholar
  2. 2.
    Davies MG, Hagen PO (1997) Systemic inflammatory response syndrome. Br J Surg 84: 920–935PubMedCrossRefGoogle Scholar
  3. 3.
    Moldawer LL (1994) Biology of proinflammatory cytokines and their antagonists. Crit Care Med 22: S3–S7PubMedGoogle Scholar
  4. 4.
    Christman JW (1992) Potential treatment of sepsis syndrome with cytokine specific agents. Chest 102: 613–617PubMedCrossRefGoogle Scholar
  5. 5.
    Christman JW, Holden EP, Blackwell TS (1995) Strategies for blocking the systemic effects of cytokines in the sepsis syndrome. Crit Care Med 23: 955–963PubMedCrossRefGoogle Scholar
  6. 6.
    Bernard GR (1995) Sepsis trials. Am J Resp Crit Care Med 102: 4–10Google Scholar
  7. 7.
    Dinarello CW, Wolff SM (1993) Mechanisms of disease: the role of Interleukin 1 in disease. New Engl J Med 328: 106–113PubMedCrossRefGoogle Scholar
  8. 8.
    Dinarello CA (1991) The proinflammatory cytokines Interleukin-1 and Tumor Necrosis Factor and treatment of septic shock syndrome. J Inf Dis 163: 1177–1184CrossRefGoogle Scholar
  9. 9.
    Eisemberg SP, Evans RJ, Arend WP et al (1990) Primary structure and functional expression from complementary Interleukin-1 receptor antagonist. Nature 343: 341–346CrossRefGoogle Scholar
  10. 10.
    Granowitz EV, Santos AA, Poutsaka DD et al (1991) Production of Interleukin-1 receptor antagonist during experimental endotoxemia. Lancet 1338: 1423–1424CrossRefGoogle Scholar
  11. 11.
    Ohlsson K, Bjork P, Bergenfeldt M et al (1990) Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 343: 550–552CrossRefGoogle Scholar
  12. 12.
    Arend WP (1991) Interleukin 1 receptor antagonist: a new member of Interleukin 1 family. J Clin Invest 88: 1445–1451PubMedCrossRefGoogle Scholar
  13. 13.
    Fisher E, Marana MA, Van Zee KJ et al (1992) Interleukin-1 receptor antagonist improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. J Clin Invest 89: 1551–1557CrossRefGoogle Scholar
  14. 14.
    Fisher CJ, 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 multicentre trial. Crit Care Med 22: 12–21PubMedGoogle Scholar
  15. 15.
    Fisher CJ, 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 blind, placebo-controlled trial. JAMA 271: 1836–1843PubMedCrossRefGoogle Scholar
  16. 16.
    Knaus WA, Harreil FE, LeBreque JF et al (1996) Use of predicted risk of mortality to evaluate the efficacy of anticytokine therapy in sepsis. Crit Care Med 24: 46–56PubMedCrossRefGoogle Scholar
  17. 17.
    Bazzoni F, Beutler B (1996) Seminars in medicine at the Beth Israel Hospital, Boston: The tumour necrosis factor ligand and receptor families. New Engl J Med 34: 1717–1725Google Scholar
  18. 18.
    Sorkine P, Setton A, Halpern P. et al (1995) Soluble tumour necrosis factor receptors reduce bowel ischemia-induced lung permeability and neutrophil sequestration. Crit Care Med 23: 1377–1381PubMedCrossRefGoogle Scholar
  19. 19.
    Van Zee KJ, Kohno T, Fisher E et al (1992) Tumour necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumour necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci USA 89: 4845–4849PubMedCrossRefGoogle Scholar
  20. 20.
    Mohler KM, Torrance DS, Smith CA et al (1993) Soluble tumour necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 151: 1548–1561PubMedGoogle Scholar
  21. 21.
    Fisher CJ, Agosti JA, Opal SM et al (1996) Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. New Engl J Med 334: 1697–1702PubMedCrossRefGoogle Scholar
  22. 22.
    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. A randomized controlled multicenter trial. JAMA 277: 1531–1538PubMedCrossRefGoogle Scholar
  23. 23.
    Bone RC (1992) Phospholipids and their inhibitors: a critical evaluation of their role in the treatment of sepsis. Crit Care Med 20: 884–890PubMedCrossRefGoogle Scholar
  24. 24.
    Lefer A (1989) Significance of lipid mediators in shock states. Circ Shock 27: 3–12PubMedGoogle Scholar
  25. 25.
    Sun X, Hsueh W (1988) Bowel necrosis induced by tumour necrosis factor in rats is mediated by platelet activating factor. J Clin Invest 81: 1328–1331PubMedCrossRefGoogle Scholar
  26. 26.
    Sun X, Hsueh W, Torre-Amione G (1990) Effects of in vivo priming on endotoxin induced hypotension and tissue injury: the role of PAF and tumour necrosis factor. Am J Pathol 136: 949–956PubMedGoogle Scholar
  27. 27.
    Kubes P, Suzuki M, Granger N (1990) Platelet activating factor-induced microvascular dysfunction: role of adherent leukocytes. Am J Physiol 21: G158–G163Google Scholar
  28. 28.
    Kubes P, Ibbotson G, Russel J et al (1990) Role of platelet activating factor in ischemia/reperfusion induced leukocyte adherence. Gastroint Liver Physiol 259: G300–G305Google Scholar
  29. 29.
    Thompson WA, Coyle S, Van Zee K et al (1994) The metabolic effects of platelet activating factor in endotoxemic man. Arch Surg 129: 72–79PubMedCrossRefGoogle Scholar
  30. 30.
    Dhainaut JFA, Tenaillon A, Le Tulzo Y et al (1994) Platelet-activating factor antagonist BN 52021 in the treatment of severe sepsis: a randomized, double-blind, placebo-controlled, multicenter clinical trial. Crit Care Med 22: 1720–1728PubMedGoogle Scholar
  31. 31.
    Cohen J, Carlet J for the INTERSEPT group (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
  32. 32.
    Rheinhart K, Wiegand-Lohnert C, Grimminger F et al (1996) Assessment of the safety and efficacy of the monoclonal anti-tumour necrosis factor antibody fragment, MAK 195F, in patients with sepsis and septic shock: a muticenter, randomized, placebo-controlled, dose ranging study. Crit Care Med 24: 733–742CrossRefGoogle Scholar
  33. 33.
    Silva AT, Bayston KF, Cohen J (1990) Prophylactic and therapeutic effects of a monoclonal antibody to tumour necrosis factor-alpha in experimental Gram-shock. J Inf Dis 162: 421–427CrossRefGoogle Scholar
  34. 34.
    Exley AR, Cohen J, Buurman WA et al (1990) Monoclonal antibody to TNF in severe septic shock. Lancet 335: 1275–1277PubMedCrossRefGoogle Scholar
  35. 35.
    Sprung CL, Eidelman LA, Pizov R et al (1997) Influence of alterations in forgoing life-sustaining treatment practices on clinical sepsis trial. Crit Care Med 25: 383–387PubMedCrossRefGoogle Scholar
  36. 36.
    Tanaka N, Murata A, Ken-ichi U et al (1995) Interleukin 1 receptor antagonist modifies the changes to vital organs induced by acute necrotizing pancreatitis in a rat experimental model. Crit Care Med 23: 901–908PubMedCrossRefGoogle Scholar
  37. 37.
    Vincent JL, Bakker J, Marecaux G et al (1992) Administration of anti TNF antibodies improves left ventricular function in septic shock patients: results of a pilot study. Chest 101: 810–815PubMedCrossRefGoogle Scholar
  38. 38.
    Moreland LA, Baumgartner SW, Schiff MH et al (1997) Treatment of rheumatoid arthritis with a recombinant human tumour necrosis factor receptor (p75)-Fc fusion protein. New Engl J Med 337: 141–147PubMedCrossRefGoogle Scholar
  39. 39.
    Bellomo R (1992) The cytokine network in the critically ill. Anesth Intens Care 20: 288–302Google Scholar
  40. 40.
    Cavaillon JM, Munoz C, Fitting C et al (1992) Circulating cytokines: the tip of the iceberg? Circ Shock 38: 145–152PubMedGoogle Scholar
  41. 41.
    Pilz G, Fraunberger P, Appel R et al (1996) Early prediction of outcome in score-identified, postcardiac surgical patients at high risk for sepsis, using soluble tumour necrosis factor receptor-p55 concentration. Crit Care Med 24: 596–600PubMedCrossRefGoogle Scholar
  42. 42.
    Borrelli E, Roux-Lombard P, Grau GE et al (1996) Plasma concentrations of cytokines, their soluble receptors and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit Care Med 24: 392–397PubMedCrossRefGoogle Scholar
  43. 43.
    Endo S, Inada K, Yamada Y et al (1996) Plasma levels of Interleukin receptor antagonist (IL-lra) and severity of illness in patients with burns. J Med 27: 57–71PubMedGoogle Scholar
  44. 44.
    Mandrup-Poulsen T, Wogensen LD, Jensen M et al (1995) Circulating Interleukin 1 receptor antagonist concentrations are increased in adult patients with thermal injury. Crit Care Med 23: 26–33PubMedCrossRefGoogle Scholar
  45. 45.
    Goldie AS, Fearon KC, Ross JA et al (1995) Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome. JAMA 274: 172–177PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia, Milano 1998

Authors and Affiliations

  • G. Berlot
  • M. Soiat

There are no affiliations available

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