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(Journal of Leukocyte Biology. 2001;69:921-927.)
© 2001 by Society for Leukocyte Biology

Superantigen antagonist blocks Th1 cytokine gene induction and lethal shock

Gila Arad, Dalia Hillman, Revital Levy and Raymond Kaempfer

Department of Molecular Virology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

Correspondence: Dr. Raymond Kaempfer, Department of Molecular Virology, The Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel. E-mail: kaempfer{at}cc.huji.ac.il

Bacterial superantigens trigger an excessive, Th1-cytokine response leading to toxic shock. We designed a peptide antagonist that inhibits SEB-induced expression of human genes for IL-2, IFN-{gamma}, and TNF-ß, cytokines that mediate shock. The peptide antagonist shows homology to a ß-strand-hinge-{alpha}-helix domain that is conserved structurally in superantigens produced by Staphylococcus aureus and Streptococcus pyogenes yet remote from known binding sites for the major histocompatibility class II molecule and T-cell receptor. For Th1-cell activation, superantigens depend on this domain. The peptide protected mice against lethal challenge with SEB or SEA. Moreover, it rescued mice undergoing toxic shock. Surviving mice rapidly developed broad-spectrum, protective immunity, which rendered them resistant to further lethal challenges with different staphylococcal and streptococcal superantigens. Thus, the lethal effect of superantigens, mediated by Th1 cytokines, can be blocked with a peptide antagonist that inhibits their action at the top of the toxicity cascade, before activation of T cells takes place.

Key Words: toxic shock • T-cell activation • antagonist peptide • protective immunity




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