LINOMIDE, A NOVEL IMMUNOMODULATOR THAT PREVENTS DEATH IN 4 MODELS OF SEPTIC SHOCK

Intravenous injections of 50 mug Staphylococcus aureus enterotoxin B ( SEB) or bacterial lipopolysaccharide (LPS) are lethal, provided that m ice are simultaneously sensitized with either N-galactosamine (GalN) o r the anti-glucocorticoid RU-38486. Similar to the synthetic glucocort icoid (GC) receptor agonist dexamethasone, pharmacological doses of th e immunomodulator linomide (quinoline-3-carboxamide) prevent death in all four models of lethal septic shock (LPS + GalN, LPS + RU-38486, SE B + GalN, and SEB + RU-38486) and inhibit the secretion of tumor necro sis factor, one of the major intermediate effector molecules of SEB an d LPS toxicity. In this system, cyclosporine A (CsA), although effecti ve in suppressing SEB toxicity, fails to counteract the lethal effect of LPS. This observation, together with the fact that linomide acts in the presence of excess amounts of GC receptor antagonist, indicates t hat linomide functions in a different way to that of known immunosuppr essive agents like CsA and GC.