The Antirheumatic Drug Gold, a Coin With Two Faces: AU(I) and AU(III). Desired and Undesired Effects on the Immune System.
Three new findings are reviewed that help to understand the mechanisms of action of antirheumatic Au(I) drugs, such as disodium aurothiomalate (Na(2)Au(I)TM): (i) We found that Na(2)Au(I)TM selectively inhibits T cell receptor (TCR)-mediated antigen recognition by murine CD(4+) T cell hybridomas specific for antigenic peptides containing at least two cysteine residues. Presumably, Au(I) acts as a chelating agent forming linear complexes (Cys-Au(I)-Cys) which prevent correct antigen-processing and/or peptide recognition by the TCR. (ii) We were able to show that Au(I) is oxidized to Au(III) in phagocytic cells, such as macrophages. Because Au(III) 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 OCl(-) and inactivates lysosomal enzymes. (iii) Pretreatment with Au(III) of a model protein antigen, bovine ribonuclease A (RNase A), induced novel antigenic determinants recognized by CD(4+) T lymphocytes. Analysis of the fine specificity of these 'Au(III)-specific' T cells revealed that they react to RNase peptides that are not presented to T cells when the native protein, i.e., not treated with Au(III), is used as antigen. The T cell recognition of these cryptic peptides did not require the presence of gold. This finding has important implications for understanding the pathogenesis of allergic and autoimmune responses induced by Au(I) drugs. Taken together, our findings indicate that Au(I) and Au(III) each exert specific effects on several distinct components of macrophages and the subsequent activation of T cells; these effects may explain both the desired anti-inflammatory and the adverse effects of antirheumatic gold drugs.
Takahashi
K
K
Division of Immunology Medical Institute of Environmental Hygiene Heinrich Heine University Düsseldorf Auf'm Hennekamp 50 Düsseldorf D-40225 Germany.
Griem
P
P
Goebel
C
C
Gonzalez
J
J
Gleichmann
E
E