Immunomodulatory effects of therapeutic gold compounds. Gold sodium thiomalate inhibits the activity of T cell protein kinase C (original) (raw)
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Effect of the thiol group on experimental gold-induced autoimmunity
Arthritis & Rheumatism, 2010
Brown Norway rats injected with aurothiopropanolsulfonate sodium salt develop systemic autoimmunity. The aim of this study was to assess the influence of the sulfur-containing group in this experimental model of gold-induced autoimmunity. It was shown that the sulfur-containing group does not induce autoimmunity of itself, but potentiates the immunotoxic effects of gold. Rheumatoid arthritis patients treated with gold salts occasionally develop immunologically mediated side effects, including membranous glomerulopathy (for review, see ref. 1). These manifestations have
Journal of Clinical Investigation, 1994
Endothelial adhesion molecules play an important role in the tissue recruitment of leukocytes in inflammatory conditions such as rheumatoid arthritis. We have investigated the effect of the antirheumatic drug gold sodium thiomalate on adhesion molecule protein and mRNA expression in cultured human endothelial cells. Gold sodium thiomalate inhibited cytokine (TNF, IL-1, IL-4)-stimulated expression of vascular cell adhesion molecule-i and E-selectin but not intercellular adhesion molecule-i on endothelial cells. Gold sodium thiomalate also suppressed TNF-stimulated increases in vascular cell adhesion molecule-i and E-selectin mRNA levels but had no effect on intercellular adhesion molecule-i mRNA. Thiomalate (mercaptosuccinate), but not gold thioglucose or D-penicillamine, mimics the effect of gold sodium thiomalate at equimolar concentrations. We propose that the inhibition of vascular cell adhesion molecule-i and E-selectin expression by gold sodium thiomalate is due to its thiomalate and not its gold component. Gold sodium thiomalate has a direct effect on endothelial adhesion molecule expression, and this may contribute to its antiinflammatory activity. (J.
European Journal of Immunology, 2001
Gold salts are beneficial in the treatment of rheumatoid arthritis but may induce immunemediated disorders in predisposed patients. Gold salts induce Th2-dependent autoimmunity in Brown-Norway (BN) rats but not in Lewis (LEW) rats. The aim of this study was to define molecular targets of gold salts and to approach why LEW rats are resistant. Gold salts act on early steps of transduction in T cells from BN and LEW rats since they trigger tyrosine phosphorylation of numerous proteins including p56 lck and a calcium signal which results in IL-4 and IFN-+ expression by BN and LEW T cells. However, the IL-4 response was favored in BN spleen cells in vitro and in vivo. IFN-+ , produced in part by CD8 + cells, contributes to the resistance of LEW rats since gold salt-injected LEW rats receiving anti-CD8 or anti-IFN-+ mAb displayed the parameters characteristics of gold salt-induced Th2 autoimmunity although to a lesser extent than in BN rats. Gold salts transduce a signal in BN and LEW spleen cells resulting in IL-4 and IFN-+ gene transcription with a preferential IL-4 response in BN rats, a Th2-prone strain, while IFN-+ contributes to the resistance of LEW rats.
Journal of Pharmaceutical Sciences, 1988
Gold sodium thirnalate is-a pale yeiow powderwhich forms a colorless solution when added to sterile water. The marketed form of gold sodium thiomalate is a pale yellow solution. The yellow color develops as a result of the sterilization process. This study demonstrates that the physical change induced in the drug by the sterilization process has no effect on the action of gold sodium thiomalate on the serine esterase thrombin, nor on the inhibition of the mixed lymphocyte response. Thus it is unlikely that the yellow component is responsible for benefit in rheumatoid arthritis. If the components creating the yellow color cause toxicity, the preparation and/or formulation of the drug should be changed.
The Journal of Immunology
Upon weekly i.m. injections of disodium gold thiomalate (Na2AuTM) 100% of A.SW mice produced IgG autoantibodies to antinuclear Ag and nucleolar Ag, respectively; about 70% of C57BL/6 mice produced IgG antinuclear Ag, whereas DBA/2 mice were resistant. Moreover, C57BL/6 mice, but not DBA/2 mice, showed increased mesangial deposits of IgG. These alterations were due not to disodium thiomalate, but to the gold ion of Na2AuTM. An assumed T cell reactivity of susceptible mouse strains to Na2AuTM was tested by means of the direct popliteal lymph node (PLN) assay. However, no distinct PLN reaction to Na2AuTM was detectable. Likewise, AuCl did not induce a PLN reaction. Both Na2AuTM and AuCl contain gold in the Au(I) state. The poor PLN responses to Au(I) contrasted with the strong PLN responses to Au(III) compounds. PLN reactions to Au(III) were dose dependent, T cell dependent, and specific. When Au(III) was reduced to Au(I) by addition of Na2TM or methionine before testing in the PLN ass...
Gold-specific T cells in rheumatoid arthritis patients treated with gold
Journal of Clinical Investigation, 1992
Gold-specific T lymphocyte clones were isolated from a patient with rheumatoid arthritis who developed delayed type hypersensitivity reactions to gold. All of the isolated T cell clones required histocompatible antigen presenting cells as well as gold for induction of proliferation. Using a panel of HLA-homozygous Epstein Barr virus-transformed B (EBV-B) cells and anti-HLA antibodies, the clones were shown to recognize gold in the context of DR1 molecules. Gold recognition did not require active antigen processing since specific proliferation was not affected by glutaraldehyde fixation of the DR1 homozygous antigen presenting cells. Furthermore, we could show that gold salts inhibited peptide-induced responses of a peptide-specific T cell clone.
Archives of Toxicology, 1995
The oxidizing capacity of phagocytic cells is suspected to play a major role in the generation of immunogenic drug metabolites, in particular those that cause extrahepatic immunopathological lesions. In the case of the antirheumatic drug gold(I) disodium thiomalate (Na2Au(I)TM), oxidation of the Au(I) ion to Au(III) appears to be responsible for the adverse immune reactions which may develop during gold therapy. Here, we show that the reactive metabolite Au(III) may be generated by mononuclear phagocytes (M~) exposed to Au(I). The generation of Au(III) was analyzed by means of the adoptive transfer popliteal lymph node assay (PLNA) in mice, using T lymphocytes previously sensitized to Au(III) as a detection probe. Donors of the Au(III)-primed T cells were either directly sensitized to Au(III) by injection of tetrachloroauric acid (HAu(III)C14), or indirectly via chronic treatment with Na2Au(I)TM. As donors of peritoneal cells (PC), we used mice which had received weekly i.m. injections of Na2Au(I)TM for 12 weeks and contained increased numbers of activated B cells. The PC of these mice were found to elicit a significant secondary response when used as antigenic material for the restimulation of Au(III)-primed T cells. The immunogenicity of PC obtained from Na2Au(I)TMtreated mice paralleled the total gold content of these