THE ANTIRHEUMATIC DRUG DISODIUM AUROTHIOMALATE INHIBITS CD4(-CELL RECOGNITION OF PEPTIDES CONTAINING 2 OR MORE CYSTEINE RESIDUES() T)

The mechanism of action of antirheumatic gold drugs, such as disodium aurothiomalate (Au(I)TM), has not been clearly identified. Gold drugs inhibit T cell activation induced by mitogen and anti-CD3 mAb in vitro at relatively high concentrations. However, since gold drugs fail to induce immunosuppression in vivo, the pharmacologic relevance of this finding is doubtful. In this study, we asked whether Au(I)TM interfere s with processing and presentation of defined Ags to T cells. Using a panel of murine CD4(+) T cell hybridomas, we found that low concentrat ions of Au(I)TM (less than or equal to 10 mu M) led to a markedly redu ced IL-2 release of T cell hybridoma clones that recognized peptides c ontaining two or more cysteine (Cys) residues, such as bovine insulin A1-14. Since disodium thiomalate alone had no effect, the inhibition w as due to Au(I). IL-2 production induced by anti-CD3 mAb stimulation w as not affected by the low concentration of Au(I)TM used. Au(I)TM had no effect on the presentation of peptides containing no or only one Cy s residue(s). In contrast to the unmodified insulin peptide A1-14, Au( I) could not inhibit recognition of an insulin peptide in which Cys re sidues in positions 6 and 11 were replaced by serine. Most likely, the observed inhibition is mediated by formation of chelate complexes bet ween Au(I) and two Cys thiol groups of the affected antigenic peptides . The peptide-specific inhibitory effect of Au(I) on Ag presentation d escribed here might contribute to the therapeutic effect of Au(I) comp ounds in rheumatoid arthritis.