Monoclonal antibody to tumor necrosis factor--alpha prevents lethal endotoxin sepsis in adult rhesus monkeys.
In a rhesus monkey endotoxin sepsis model established by intravenous administration of 300 mg/kg D-galactosamine and 0.1 microgram/kg lipopolysaccharide from Salmonella abortus equi, hemodynamic, respiratory, metabolic and hematologic variables; levels of blood gases; monkey leukocyte elastase levels, and blood plasma concentrations of tumor necrosis factor--alpha (TNF) were monitored for 6 hours after administration, and again after 24 hours. Thirty minutes after administration of lipopolysaccharide, either 15 mg/kg anti-TNF monoclonal antibody (MoAB; n = 6) or vehicle placebo (saline solution; n = 4) were given intravenously. During this short-term experiment the organ functions were not different between the treatment groups. However, anti-TNF MoAb afforded morphologic protection from heart, lung, liver, and kidney damage after lipopolysaccharide challenge. Coagulation responses (platelet count and levels of fibrinogen, antithrombin III, and thrombin-antithrombin III complex) were smaller in anti-TNF MoAB-treated monkeys. Plasma TNF levels (WEHI cell cytotoxicity assay) reached a peak (350 pg/ml) 60 minutes after lipopolysaccharide administration in vehicle control subjects but no TNF was detected in the anti-TNF MoAB-treated monkeys. All control animals died 67 +/- 30 hours after lipopolysaccharide administration from multiorgan failure. On the contrary, all anti-TNF MoAB-treated animals survived 14 days (p > 0.005 vs placebo group mortality). Thus in short-term monkey experiments our study indicates protection against lipopolysaccharide-induced endotoxin sepsis by anti-TNF MoAB, which may have clinical relevance for the treatment of human septicemia.
Fiedler
V B
VB
Pharma Research Center, Bayer AG, Wuppertal, Federal Republic of Germany.
Loof
I
I
Sander
E
E
Voehringer
V
V
Galanos
C
C
Fournel
M A
MA
D000137:Acid-Base Imbalance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001777:Blood Coagulation; D016207:Cytokines / Q000097:blood; D005688:Galactosamine / Q000494:pharmacology; D006439:Hemodynamics; D007116:Immunization, Passive; D019272:Leukocyte Elastase; D008070:Lipopolysaccharides / Q000097:blood; D008253:Macaca mulatta; D008297:Male; D010196:Pancreatic Elastase / Q000097:blood; D012119:Respiration; D012475:Salmonella; D012772:Shock, Septic / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase