Synergistic inhibition of human B cell activation by gold sodium thiomalate and auranofin

The mechanism of action of gold compounds, which are effective in the treat ment of rheumatoid arthritis RA), has not been clearly identified. Since on e of the characteristic features of RA is chronic stimulation of B cells, t he current studies compared the effects of parenteral gold (gold sodium thi omalate; GST) and orally active gold (auranofin; AUR) on human B cells. IgM production was induced from highly purified B cells obtained from healthy donors by stimulation with staphylococcus aureus Cowan I (SA) plus IL-2. T cell proliferation and IFN-gamma production was induced from highly purifie d T cells by stimulation with immobilized MAb to CD3. AUR as well as GST su ppressed B cel IgM production at much lower concentrations than those that suppressed T cell proliferation or IFN-gamma production. Thus, as little as 0.01 mu g/ml AUR (0.015 mu M) markedly suppressed IgM production but neith er T cel proliferation nor IFN-gamma production. AUR as well as GST is requ ired at the initation of cultures to exert optimal suppressive effects on I gM production. Moreover, AUR as well as GST suppressed the expression of CD 98 and CD71 on SA-stimulated B cells Of not, AUR and GST exerted a synergis tic inhibitory effect on B cell production of IgM and IgG in a manner which was reversed by catalase, but not by ascorbate. The synergistic inhibitory effect is most likely to be due to thiomalate components of GST, since AUR and thiomalate exerted comparable synergistic inhibitory effects on B cell function. Finally, AUR and bucillamine, another antirheumatic drug with th iol groups, also showed synergistic inhibition of B cell function. These re sults indicate that AUR and GST preferentially inhibit the function of B ce lls by interfering with the initial activation of B cells. More importantly , the date indicate that AUR synergizes with GST or thiols to inhibit B cel l function in a manner that depends upon the generation of hydrogen peroxid e. These synergistic inhibitory effects of AUR and compounds with thiols on in vitro human B cell activation suggest the therapeutic efficacy of combi nations of these compounds in RA. (C) 1999 Academic Press.