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The Journal of Immunology, 2000, 164: 4804-4811.
Copyright © 2000 by The American Association of Immunologists

Synthetic Endotoxin-Binding Peptides Block Endotoxin- Triggered TNF-{alpha} Production by Macrophages In Vitro and In Vivo and Prevent Endotoxin-Mediated Toxic Shock

Silke Dankesreiter*, Adolf Hoess{dagger}, Jens Schneider-Mergener{ddagger}, Hermann Wagner* and Thomas Miethke1,*

* Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany; {dagger} MorphoSys, Martinsried/Munich, Germany; and {ddagger} Institute of Medical Immunology, Humboldt University of Berlin, Berlin, Germany

Lipid A, the conserved portion of endotoxin, is the major mediator of septic shock; therefore, endotoxin-neutralizing molecules could have important clinical applications. Here we show that peptides derived from Limulus anti-LPS factor (LALF), bactericidal/permeability increasing protein (BPI) and endotoxin-binding protein, bind to lipid A and block the recombinant LALF/lipid A interaction in vitro. Because their neutralizing capacity in vitro as well as in vivo has been limited, we created hybrid peptides comprising two endotoxin-binding domains. The hybrid molecule LL-10-H-14, containing endotoxin-binding domains from LALF and endotoxin-binding protein, turned out to be the most active peptide within the series of peptides tested here to inhibit the CD14/lipid A interaction and is able in vitro to block the endotoxin-induced TNF-{alpha} release of murine macrophages up to 90%. Furthermore, LL-10-H-14 not only reduced peak serum levels of TNF-{alpha} of mice when preinjected but also reduced TNF-{alpha} levels when given 15 min after the endotoxin challenge. As compared with other peptides, only LL-10-H-14 is able to strongly decrease endotoxin-stimulated TNF-{alpha} release by human macrophage cell lines as well as by PBMC. Furthermore, the hybrid peptide is protective against endotoxin-provoked lethal shock. As such, LL-10-H-14 could have prophylactic and/or therapeutic properties in humans for the management of septic shock.







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