Drug-induced inhibition of insulin recognition by T-cells: the antirheumatic drug aurothiomalate inhibits MHC binding of insulin peptide.
Previous work has shown that the Au(I) moiety of the antirheumatic drug disodium aurothiomalate (Au(I)TM) can selectively inhibit the response of murine CD4+ T-cell hybridomas to antigenic peptides containing two or more cysteine (Cys) residues. Here, we investigated the mechanism that underlies the inhibitory effect of Au(I)TM on T-cell recognition of bovine insulin (BI). We found that low concentrations of Au(I)TM (10 microM) inhibited the BI-induced proliferation of bulk T-cells from BI-immunized BALB/c mice as well as the IL-2 release of Ab- and Ad-restricted T-cell hybridoma clones. Au(I)TM was found to inhibit binding of the immunodominant BI peptide A1-14 to isolated MHC class II molecules. We suggest that Au(I) forms stable chelate complexes with thiol groups of two Cys residues in the BI A1-14 peptide. Conceivably, formation of these metal-peptide complexes keeps the peptide in a sterical conformation that cannot undergo binding to MHC class II molecules, resulting in an inhibition of T-cell activation due to insufficient peptide presentation.
Division of Immunology, Medical Institute of Environmental Hygiene, Düsseldorf, Germany.
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K
Takahashi
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H
Kropshofer
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Vogt
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E
Gleichmann
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P
Griem
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D018501:Antirheumatic Agents / Q000494:pharmacology*; D002999:Clone Cells; D005260:Female; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006183:H-2 Antigens / Q000378:metabolism; D006649:Histocompatibility Antigens / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*
D018501:Antirheumatic Agents; D006183:H-2 Antigens; C108513:H-2A antigen; D006649:Histocompatibility Antigens; D000949:Histocompatibility Antigens Class II; D007328:Insulin; D010446:Peptide Fragments; D006052:Gold Sodium Thiomalate