THE ANTIRHEUMATIC DRUG GOLD - DESIRED AND NOT DESIRED REACTIONS OF AU(I) AND AU(II) ON THE IMMUNE-SYSTEM

Three new findings are reviewed that help to understand the mechanisms of action of antirheumatic gold drugs, such as disodium aurothiomalat e (Na2Au(I)TM): i) We found that Na2Au(I)TM selectively inhibits T-cel l receptor-mediated antigen recognition by murine CD4(+) T-cell hybrid omas specific for antigenic peptides containing at least two cysteine residues. Presumably, Au(I) acts as a chelating agent forming linear c omplexes (Cys-Au(I)-Cys) which prevents correct antigen-processing and /or peptide recognition by the T-cell receptor. ii) We were able to sh ow that Au(I) is oxidized to Au(III) in mononuclear phagocytes, such a s macrophages. Because Au(III) rapidly oxidizes protein and itself is re-reduced to Au(I), this may introduce an Au(I)/Au(III) redox system into phagocytes which scavenges reactive oxygen species, such as hypoc hlorous acid (HOCl) and inactivates lysosomal enzymes. iii) Pretreatme nt with Au(III) of a model protein antigen, bovine ridonuclease A (RNa se A), induced novel antigenic determinants recognized by CD4(+) T lym phocytes. Analysis of the fine specificity of these ''Au(III)-specific '' T-cells revealed that they react to RNase peptides that are not pre sented to T-cells when the native protein, i.e., not treated with Au(I II), is used as antigen. The T-cell recognition of these cryptic pepti des did not require the presence of gold. This finding has important i mplications for understanding the pathogenesis of allergic and autoimm une responses induced by gold drugs. Taken together, our findings indi cate that Au(I) and Au(III) each exert specific effects on several dis tinct functions of macrophages and the activation of T-cells. These ef fects may explain both the desired anti-inflammatory and the adverse e ffects of antirheumatic gold drugs.