Three new findings are reviewed that help to understand the mechanisms of
action of antirheumatic Au(I) drugs, such as disodium aurothiomalate (Na2Au(I)TM):
(i) We found that Na2Au(I)TM selectively inhibits T cell receptor (TCR)-mediated
antigen recognition by murine CD4+ 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
CD4+ 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.
