SUMMARY Thalidomide isaneffective immunomodulatory druginman, butits mechanism ofaction remains unclear. We hypothesized that, inaddition toitsreported inhibitory effects on production of monocyte-derived tumournecrosis factor-alpha (TNF-a), thalidomide mightbeeffective atthe level ofThimmunoregulation. Ina comparative study withtheimmunosuppressant cyclosporin A,we havedemonstrated a potentandspecific effect ofthalidomide on cytokine production relating tothedistinct ThlandTh2subsets. Itinduced andenhanced theproduction ofIL-4and IL-5and,atthesame dose(1000 ng/ml), significantly inhibited interferon-gamma (IFN-'y) production inphytohaemagglutinin (PHA)-stimulated humanperipheral bloodmononuclear cell (PBMC)cultures. Stimulation ofPBMC withrecall antigen (streptokinase: streptodornase (SKSD)) at144hintheabsence ofthalidomide resulted inapredominantly Thlresponse,withthe production ofIFN--y andIL-2. Thalidomide switched this responsefromaThItoaTh2type.The effect was mostpronounced at1000ng/mlthalidomide, whereinhibition ofIFN--y andenhancementofIL-4production was maximal. Inunstimulated cultures thalidomide alone induced IL-4 production. Cyclosporin A,incontrast, inhibited bothThlandTh2cytokine production byPHAstimulated PBMC. Timecourse datafromthalidomide-treated cultures revealed thatthe augmented IL-4production diminished astheculture timeincreased, whereas IFN--y production was significantly increased. Thisresponsemightbeduetoactivation-induced
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