Therapeutic neutralization of interferon-gamma in primates prevents lethality in Gram-negative bacteremic shock

Background

The treatment of severe sepsis and septic shock with anticytokine therapies remains a dilemma. Although a number of preclinical studies have shown efficacy in primate models of bacteremic shock when administered prophylactically, these same therapies have a much diminished effectiveness when administered therapeutically.

Aim

This study investigated whether therapeutic administration of a novel antihuman interferon-gamma (anti-IFNγ) monoclonal antibody (mAb) could improve outcome in a lethal model of Gram-negative bacteremic shock.

Methods

Gram-negative bacteremic shock was induced in 14 anesthetized Cynomolgus monkeys by intravenous injection of approximately 10 (10) cfu live Escherichia coli. Treatment was administered only after the animals developed symptoms of shock meeting at least two of the predefined criteria: 30% reduction in blood pressure, 30% increase in heart rate and oliguria (urine output <1 ml/kg body weight/hour). Six of the animals received placebo while eight were treated with 10 mg/kg humanized anti-IFNγ mAb. Invasive hemodynamic monitoring under anesthesia was continued for 12 hours, after which the animals were returned to their cages, and were followed daily for clinical signs during 14 days.

Results

Five out of the six placebo-treated Cynomolgus monkeys died or required euthanasia within 24–72 hours after E. coli challenge, while one animal survived for 5 days. In contrast, six of the eight animals treated with the humanized anti-IFNγ mAb survived for 7–14 days (P = 0.013 vs placebo). More specifically within the treated group, two animals died early of sepsis (day 3 and day 4, respectively), two animals were euthanized on day 7 because of limb necrosis (caused by catheter-related thrombosis) and not directly because of the sepsis symptoms, one animal was euthanized on day 9 due to sepsis symptoms, and three animals survived 14 days and appeared to be in good health. Treatment with the anti-IFNγ mAb decreased the systemic TNF-α, IL-6 and IL-1β response to E. coli. Furthermore, renal dysfunction, evidenced by increased creatinine, was significantly decreased by treatment with the anti-IFNγ mAb.

Conclusions

This study demonstrates that, in a primate model of E. coli-induced septic shock, the neutralization of IFNγ with a mAb, administered after the onset of clinical signs of sepsis, improves survival and attenuates the pathological changes associated with the development of multiple organ dysfunction. This suggests that IFNγ blockade potentially represents an effective mode of intervention in lethal septic shock.