Regulation of B cell function by bucillamine, a novel disease-modifying antirheumatic drug

Bucillamine [N-(2-mercapto-2-methylpropionyl)-L-cysteine] (BUC) is a thiol compound that differs from D-penicillamine (DPC) in that it contains two free sulfhydryl groups. Clinical trials have demonstrated that its efficacy in rheumatoid arthritis is superior to that of DPC, but its mechanism of action remains unclear. We therefore examined the effects of BUC on the in vitro function of human B cells in comparison to those of DPC. IgM production was induced from highly purified B cells from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus factors generated from mitogen-activated T cells (TF) or interleukin-2 (IL-2) or with immobilized anti-CD3-activated CD4+ T cells. BUC suppressed the production of IgM at concentrations of 0.3-100 micrograms/ml irrespective of the presence of CuSO4. Whereas BUC suppressed the production of IL-2 and interferon-gamma by immobilized anti-CD3-activated CD4+ T cells, its suppressive effects on the production of IgM in anti-CD3-stimulated cultures were not overcome by addition of TF or IL-2, indicating that the action of BUC involves direct inhibition of B cell function. BUC suppressed the initial stages of B cell activation, but not the maturation of previously activated B cells. In contrast to DPC, the suppressive activities of BUC did not require the presence of copper and were not overcome by the addition of monocytes or catalase. The effects of SA981, a metabolite of BUC with an intramolecular disulfide, on B cell function were more marked than those of BUC, whereas the effects of SA679, another metabolite of BUC with one of the two sulfhydryl bonds methylated, were similar to those of DPC. SA672, a metabolite of BUC with both of the two sulfhydryl bonds methylated, did not suppress B cell function. These results indicate that BUC as well as some of its metabolites inhibit cytokine production by T cells and also suppress the production of IgM at least in part by directly inhibiting B cells. These compounds exert immunosuppressive effects that are similar to those of DPC, but also unique inhibitory effects that depend upon the capacity of BUC to form an intramolecular disulfide between its two sulfhydryl groups.