Inhibition of lipopolysaccharide-associated endotoxin activities in vitro and in vivo by the human anti-lipid A monoclonal antibody SdJ5-1.17.15.
The present study evaluated the effect of a novel anti-lipid A monoclonal antibody, termed SdJ5, on the in vitro production of tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta by endotoxin- or lipopolysaccharide (LPS)-challenged human peripheral blood mononuclear cells (hPBMC). In addition, the present study determined whether SdJ5 could neutralize the in vivo toxicity of LPS. SdJ5, at a concentration equal to or greater than 3 micrograms/ml, specifically inhibited TNF-alpha and interleukin-1 beta production by hPBMC stimulated with every type of LPS and lipid A assessed. SdJ5 also showed a significantly greater inhibition of cytokine production than a nonrelevant human immunoglobulin M myeloma control. The SdJ5-mediated inhibition of TNF-alpha production was rapid, as the simultaneous addition of the SdJ5 and LPS still resulted in a marked decrease in hPBMC cytokine synthesis. The ability of SdJ5 to neutralize in vivo toxicity was also determined by using LPS from four different strains of gram-negative bacteria. LPS, when preincubated with SdJ5, resulted in a significant decrease in the 24-h mortality rate compared with that for the control. These studies show that the anti-lipid A monoclonal antibody SdJ5 can modulate LPS-induced cytokine production in vitro and increase the survival rate of rats challenged with lethal doses of LPS.
Fang
I S
IS
Hyland Division, Baxter Healthcare Corporation, Duarte, California 91010.
Wisniewski
M A
MA
Huntenburg
C C
CC
Knight
L S
LS
Bubbers
J E
JE
Schneidkraut
M J
MJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D008050:Lipid A / Q000276:immunology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D007375:Interleukin-1; D008050:Lipid A; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha