The immunosuppressive effect of methimazole on cell-mediated immunity is mediated by its capacity to inhibit peroxidase and to scavenge free oxygen radicals.
We have investigated the effect of methimazole (MMI) on cell-mediated immunity and ascertained the mechanisms of immunosuppression produced by the drug. Methimazole (greater than or equal to 10(-5) M) produced a dose-dependent inhibition in 'active' (early) rosette formation with sheep red cells and in phytohaemagglutinin (PHA)-induced lymphocyte transformation. A concentration of 10(-4) M MMI inhibited the immediate rise in intracellular cAMP triggered by PHA and the subsequent time dependent decrement over 24 h. The drug (10(-3) M) also exerted a significant inhibitory effect on antibody-dependent cell-mediated cytotoxicity (ADCC) over six-fold difference in target/effector cell ratios. At a concentration of 10(-5) M, MMI inhibited zymosan-induced respiratory burst (determined by change in the chemiluminescence of oxidized luminol) in polymorphonuclear and mononuclear cell preparations. Ninety-five per cent of the chemiluminescence in the latter preparation was due to monocytes. At concentrations between 10(-7) and 10(-6) M, MMI significantly inhibited (in cell-free systems) horseradish peroxidase-dependent generation of chemiluminescence as well as the oxidation of luminol by hydrogen peroxide. Methimazole exerts its inhibitory effects on measures of cell-mediated immunity by at least two mechanisms: inhibition of peroxidase and scavenging free oxygen radicals. Insensitivity of the test systems or poor access of MMI to leucocytes may account for the need for greater than or equal to 10(-5) M MMI to inhibit cell-mediated immunity significantly.
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000242:Cyclic AMP / Q000032:analysis; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D007165:Immunosuppression Therapy; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008713:Methimazole / Q000494:pharmacology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D012756:Sheep
D010835:Phytohemagglutinins; D008713:Methimazole; D000242:Cyclic AMP