Superantigen antagonist blocks Th1 cytokine gene induction and lethal shock

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-beta, cytokines tha t mediate shock, The peptide antagonist shows homology to a beta -strand-hi nge-alpha -helix domain that is conserved structurally in superantigens pro duced by Staphylococcus aureus and Streptococcus pyogenes yet remote from k nown binding sites for the major histocompatibility class II molecule and T -cell receptor, For Th1-cell activation, superantigens depend on this domai n. The peptide protected mice against lethal challenge with SEE or SEA. Mor eover, it rescued mice undergoing toxic shock. Surviving mice rapidly devel oped broad-spectrum, protective immunity, which rendered them resistant to further lethal challenges with different staphylococcal and streptococcal s uperantigens. Thus, the lethal effect of superantigens, mediated by Th1 cyt okines, can be blocked with a peptide antagonist that inhibits their action at the top of the toxicity cascade, before activation of T cells takes pla ce.