Delayed neutralization of interferon-gamma prevents lethality in primate Gram-negative bacteremic shock

OBJECTIVE: Whether anticytokine 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-gamma monoclonal antibody could improve outcome and reduce organ injury in a lethal model of Escherichia coli bacteremia, when administered after the onset of shock.

DESIGN: Randomized, prospective, double-blinded intervention study.

SUBJECTS: Cynomolgus monkeys.

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

MEASUREMENTS AND MAIN RESULTS: Five of the six vehicle-treated monkeys died or were killed within 24-72 hrs after E. coli administration, and all died within 5 days. In contrast, six of the eight animals treated with the anti-interferon-gamma survived for 7 days, and three of the eight animals survived 14 days (p = .013 vs. vehicle). Delayed treatment with the anti-interferon-gamma 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 < .05) and the magnitude of the inflammatory cytokine response (p < .05).

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