Induction of long-term lipopolysaccharide tolerance by an agonistic monoclonal antibody to the toll-like receptor 4/MD-2 complex.
We have established an agonistic monoclonal antibody, UT12, that induces stimulatory signals comparable to those induced by lipopolysaccharide (LPS) through Toll-like receptor 4 and MD-2. UT12 activated nuclear factor kappaB and induced the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in peritoneal exudative cells. In addition, mice injected with UT12 rapidly fell into endotoxin shock concomitant with the augmentation of serum TNF-alpha and IL-6 levels, followed by death within 12 h. On the other hand, when the mice were pretreated with a sublethal dose of UT12, the mice survived the subsequent lethal LPS challenges, with significant suppression of serum TNF-alpha and IL-6, indicating that UT12 induced tolerance against LPS. This effect of UT12 was maintained for at least 9 days. In contrast, the tolerance induced by LPS continued for less than 3 days. These results illuminate a novel potential therapeutic strategy for endotoxin shock by the use of monoclonal antibodies against the Toll-like receptor 4/MD-2 complex.
Ohta
Shoichiro
S
Department of Immunology, Saga Medical School, 5-1-1 Nabeshima, Saga, Saga 849-8501, Japan. sho@bigfoot.com
Bahrun
Uleng
U
Shimazu
Rintaro
R
Matsushita
Hidetomo
H
Fukudome
Kenji
K
Kimoto
Masao
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D007108:Immune Tolerance / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D051218:Lymphocyte Antigen 96 / Q000819:agonists / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D011485:Protein Binding / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4