Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation.
Superantigens trigger an excessive cellular immune response, leading to toxic shock. We have designed a peptide antagonist that inhibits superantigen-induced expression of human genes for interleukin-2, gamma interferon and tumor necrosis factor-b, which are cytokines that mediate shock. The peptide shows homology to a b-strand-hinge-a-helix domain that is structurally conserved in superantigens, yet is remote from known binding sites for the major histocompatibility class II molecule and T-cell receptor. Superantigens depend on this domain for T-cell activation. The peptide protected mice against lethal challenge with staphylococcal and streptococcal superantigens. Moreover, it rescued mice undergoing toxic shock. Surviving mice rapidly developed protective antibodies against superantigen that rendered them resistant to further lethal challenges, even with different superantigens. Thus, the lethal effect of superantigens can be blocked with a peptide antagonist that inhibits their action at the beginning of the toxicity cascade, before activation of T cells takes place.
Arad
G
G
Department of Molecular Virology, The Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel.
Levy
R
R
Hillman
D
D
Kaempfer
R
R
D000595:Amino Acid Sequence; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D001665:Binding Sites; D002478:Cells, Cultured; D017124:Conserved Sequence; D003429:Cross Reactions; D004768:Enterotoxins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology / Q000633:toxicity; D005098:Exotoxins / Q000276:immunology / Q000633:toxicity; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D011817:Rabbits; D012772:Shock, Septic / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy; D013211:Staphylococcus aureus / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology; D018089:Superantigens / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D013997:Time Factors
D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D005098:Exotoxins; D008565:Membrane Proteins; D009842:Oligopeptides; C117980:SpeA protein, Streptococcus pyogenes; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal; C027951:erythrogenic toxin; C026066:enterotoxin A, Staphylococcal; C031818:enterotoxin B, staphylococcal