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Antagonistic antibody prevents toll-like receptor 2–driven lethal shock-like syndromes
Guangxun Meng, … , Hermann Wagner, Carsten J. Kirschning
Guangxun Meng, … , Hermann Wagner, Carsten J. Kirschning
Published May 15, 2004
Citation Information: J Clin Invest. 2004;113(10):1473-1481. https://doi.org/10.1172/JCI20762.
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Categories: Article Infectious disease

Antagonistic antibody prevents toll-like receptor 2–driven lethal shock-like syndromes

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Abstract

Hyperactivation of immune cells by bacterial products through toll-like receptors (TLRs) is thought of as a causative mechanism of septic shock pathology. Infections with Gram-negative or Gram-positive bacteria provide TLR2-specific agonists and are the major cause of severe sepsis. In order to intervene in TLR2-driven toxemia, we raised mAb’s against the extracellular domain of TLR2. Surface plasmon resonance analysis showed direct and specific interaction of TLR2 and immunostimulatory lipopeptide, which was blocked by T2.5 in a dose-dependent manner. Application of mAb T2.5 inhibited cell activation in experimental murine models of infection. T2.5 also antagonized TLR2-specific activation of primary human macrophages. TLR2 surface expression by murine macrophages was surprisingly weak, while both intra- and extracellular expression increased upon systemic microbial challenge. Systemic application of T2.5 upon lipopeptide challenge inhibited release of inflammatory mediators such as TNF-α and prevented lethal shock-like syndrome in mice. Twenty milligrams per kilogram of T2.5 was sufficient to protect mice, and administration of 40 mg/kg of T2.5 was protective even 3 hours after the start of otherwise lethal challenge with Bacillus subtilis. These results indicate that epitope-specific binding of exogenous ligands precedes specific TLR signaling and suggest therapeutic application of a neutralizing anti-TLR2 antibody in acute infection.

Authors

Guangxun Meng, Mark Rutz, Matthias Schiemann, Jochen Metzger, Alina Grabiec, Ralf Schwandner, Peter B. Luppa, Frank Ebel, Dirk H. Busch, Stefan Bauer, Hermann Wagner, Carsten J. Kirschning

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Figure 1

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Application of mAb T2.5 for specific detection of TLR2. (A–D) Results of...
Application of mAb T2.5 for specific detection of TLR2. (A–D) Results of flow cytometry of HEK293 cells stably overexpressing Flag-tagged mTLR2 (A) or human TLR2 (B), as well as primary TLR2–/– (C) and wild-type murine macrophages (D), by staining with mAb T2.5 (bold line). Negative controls represent cells incubated with a mouse IgG-specific secondary antibody only (filled areas). For positive controls, Flag-specific (A and B) and mTLR2-specific (C and D) polyclonal antisera were used (thin line). (E) For immunoprecipitation with T2.5, lysates of HEK293 cells overexpressing murine or human TLR2, as well as of murine RAW264.7 macrophages, were applied as indicated. TLR2 precipitates were visualized by application of Flag-specific (HEK293) or mTLR2-specific (RAW264.7) polyclonal antisera. Flag-specific beads (αFlag) and protein G beads in the absence of antibodies (pG), as well as vector-transfected HEK293 cells, were used as controls. The size of TLR2 was 97 kDa.
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ISSN: 0021-9738 (print), 1558-8238 (online)

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