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.


METHODS
Randomized, prospective, double-blinded intervention study.


METHODS
Cynomolgus monkeys.


METHODS
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.


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.
Lainée
Pierre
P
C.I.T., Evreux, France.
Efron
Philip
P
Tschoeke
Sven K
SK
Elies
Laetitia
L
De Winter
Hilde
H
Lorré
Katrien
K
Moldawer
Lyle L
LL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016470:Bacteremia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000097:blood; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000097:blood; D008252:Macaca fascicularis; D012016:Reference Values; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D016207:Cytokines; D007371:Interferon-gamma