THE IMMUNOSUPPRESSIVE EFFECT OF METHIMAZOLE ON CELL‐MEDIATED IMMUNITY IS MEDIATED BY ITS CAPACITY TO INHIBIT PEROXIDASE AND TO SCAVENGE FREE OXYGEN RADICALS

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Abstract
We have investigated the effect of methimazole (MMI) on cell-mediated immunity and ascertained the mechanisms of immunosuppression produced by the drug. Methimazole (≥ 10−5m) 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 ≥ 10−5m MMI to inhibit cell-mediated immunity significantly.