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Clinical and Vaccine Immunology, October 2006, p. 1131-1136, Vol. 13, No. 10
1071-412X/06/$08.00+0     doi:10.1128/CVI.00173-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Induction of Long-Term Lipopolysaccharide Tolerance by an Agonistic Monoclonal Antibody to the Toll-Like Receptor 4/MD-2 Complex

Shoichiro Ohta,^1* Uleng Bahrun,¹ Rintaro Shimazu,² Hidetomo Matsushita,^1,2, Kenji Fukudome,¹ and Masao Kimoto¹

Departments of Immunology,¹ Otorhinolaryngology, Saga Medical School, 5-1-1 Nabeshima, Saga, Saga 849-8501, Japan²

Received 19 April 2006/ Returned for modification 6 June 2006/ Accepted 7 August 2006

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 B and induced the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-) 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- 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- 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.

Present address: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, Saga 849-8501, Japan.

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