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 that mediate shock. The peptide antagonist shows homology to a beta-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.
Arad
G
G
Department of Molecular Virology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Hillman
D
D
Levy
R
R
Kaempfer
R
R
D020816:Amino Acid Motifs; D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology / Q000633:toxicity*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D004768:Enterotoxins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology / Q000633:toxicity; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012772:Shock, Septic / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology*; D013329:Structure-Activity Relationship; D018089:Superantigens / Q000737:chemistry / Q000276:immunology / Q000633:toxicity*; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D000942:Antigens, Bacterial; D016207:Cytokines; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D010446:Peptide Fragments; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; C026066:enterotoxin A, Staphylococcal; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma