Delayed Neutralization of Interferon-γ Prevents Lethality in Primate Gram Negative Bacteremic Shock


Abstract:
Objective: Whether or not anti-cytokine therapies have a place in the treatment of severe sepsis and septic shock remains a question. Although a number of preclinical studies have shown efficacy in primate models of bacteremic shock when administered prophylactically, these same therapies have a significantly diminished effectiveness when administered therapeutically. This study investigated whether delayed administration of a novel anti-human interferon-γ monoclonal antibody could improve outcome and reduce organ injury in a lethal model of E. coli bacteremia, when administered after the onset of shock.

Design: Randomized, prospective, double-blinded intervention study in cynomolgus monkeys.

Intervention: Treatment with a humanized monoclonal antibody directed against human interferon-γ (INNO 202), administered after the onset of shock, induced by the infusion of live E. coli.

Measurements and Main Results: Five out of the six placebo-treated monkeys died or required euthanasia within 24 to 72 hours after E. coli administration, while only one animal survived for five days. In contrast, six of the eight animals treated with the anti-interferon-γ survived for seven to 14 days (p=0.013 vs placebo). Delayed treatment with the anti-interferon-γ monoclonal antibody did not restore hemodynamics or reduce the amount of crystalloid-containing fluid required to resuscitate the animals, but did attenuate renal failure (p<0.05), and the magnitude of the inflammatory cytokine response (p<0.05).

Conclusions: In a primate model of E. coli bacteremic shock, delayed neutralization of interferon-γ after the onset of shock improved survival and attenuated the pathological changes associated with the development of organ dysfunction. These findings suggest that interferon-γ blockade represents a potentially effective mode of late intervention in lethal septic shock.

Manuscript

  
  • Submitted to Critical Care Medicine
     
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    Tables
  • 1  Renal function as determined by blood urea and creatinine in E. coli bacteremic animals treated with placebo or anti-IFN-γ
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