The antirheumatic drug disodium aurothiomalate inhibits CD4+ T cell recognition of peptides containing two or more cysteine residues.
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 interferes with processing and presentation of defined Ags to T cells. Using a panel of murine CD4+ T cell hybridomas, we found that low concentrations of Au(I)TM (< or = 10 microM) led to a markedly reduced IL-2 release of T cell hybridoma clones that recognized peptides containing two or more cysteine (Cys) residues, such as bovine insulin A1-14. Since disodium thiomalate alone had no effect, the inhibition was due to Au(I). IL-2 production induced by anti-CD3 mAb stimulation was 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 Cys residue(s). In contrast to the unmodified insulin peptide A1-14, Au(I) could not inhibit recognition of an insulin peptide in which Cys residues in positions 6 and 11 were replaced by serine. Most likely, the observed inhibition is mediated by formation of chelate complexes between Au(I) and two Cys thiol groups of the affected antigenic peptides. The peptide-specific inhibitory effect of Au(I) on Ag presentation described here might contribute to the therapeutic effect of Au(I) compounds in rheumatoid arthritis.
Griem
P
P
Division of Immunology, Medical Institute of Environmental Hygiene, Heinrich Heine University Düsseldorf, Germany.
Takahashi
K
K
Kalbacher
H
H
Gleichmann
E
E
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D001030:Apamin / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology*; D002645:Chickens; D003039:Cobra Neurotoxin Proteins / Q000276:immunology; D003545:Cysteine; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005260:Female; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006183:H-2 Antigens / Q000276:immunology; D006801:Humans; D006825:Hybridomas / Q000276:immunology / Q000378:metabolism; D007328:Insulin / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009113:Muramidase / Q000276:immunology; D016853:Muromonab-CD3 / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D012260:Ribonucleases / Q000276:immunology; D013438:Sulfhydryl Compounds / Q000276:immunology*
D002614:Chelating Agents; D003039:Cobra Neurotoxin Proteins; D000939:Epitopes; D006183:H-2 Antigens; D007328:Insulin; D007376:Interleukin-2; D016853:Muromonab-CD3; D010446:Peptide Fragments; D013438:Sulfhydryl Compounds; D006052:Gold Sodium Thiomalate; D001030:Apamin; C025154:alpha-cobratoxin; D012260:Ribonucleases; D009113:Muramidase; D003545:Cysteine