Comparative inhibitory effects of bucillamine and d‐penicillamine on the function of human b cells and t cells

Abstract

Objective. Clinical trials have suggested that the efficacy of bucillamine (BUC) in rheumatoid arthritis (RA) may be superior to that of D-penicillamine (DP), although the basis of the ditferences remains unclear. Previous studies have revealed that BUC has unique immunomodulatory effects that depend upon its capacity to form an intramolecular disulfide (BUC-ID). We therefore examined the effects of BUC-ID on the in vitro function of human B cells and T cells compared with those of DP, at their pharmacologically attainable concentrations.Methods. IgM production was induced in highly purified B cells from healthy donors by stimulation with Staphylococcus aureus Cowan 1 (SAC) plus interleukin-2 (IL-2) or with immobilized anti-CDSactivated CD4+ T cells. Interferon-y (IFNy) production was induced in CD4+ T cells by stimulation with immobilized anti-CD3.Results. BUC-ID suppressed IgM production induced by SAC + IL-2 as well as that induced by immobilized anti-CDSactivated CD4+ T cells, whereas DP suppressed the latter more markedly than the former. DP (3 &ml) significantly suppressed IFNy production by immobilized anti-CD3-stimulated CD4+T cells, but not IgM production induced by SAC + IL-2 stimulation. By contrast, BUC-ID (0.3 pg/ml) significantly suppressed IgM production induced by SAC + IL-2, but not T cell IFNy production. Of note, BUC-ID did not suppress IL-6 production by SAC-activated B cells.Supported by a grant from Santen Pharmaceutical Co., Ltd., Osaka, and a grant from Manabe Medical Foundation, Tokyo, Japan.Shunsei Hirohata, MD: Teikyo University School of Medicine, Tokyo, Japan; Peter E. Lipsky, MD: Harold C. Simmons Arthritis Research Center and the University of Texas Southwestem Medical Center, Dallas, Texas.Address reprint requests to Shunsei Hirohata, MD, Second Department of Internal Medicine, Teikyo University School of Medicine, 2-1 1-1 Kaga, Itabashi-ku, Tokyo 173, Japan.Submitted for publication July 30, 1993; accepted in revised form November 3, 1993. Conclusion.These results indicate that the target cells of BUC and DP in vivo might be different, with the former inhibiting the function of B cells and the latter that of T cells. The data suggest the possibility that BUC may have a different effect in RA patients compared with the effect of DP, and may be effective in patients who do not respond to DP. Bucillamine [N-(2-mercapto-2-methylpropiony1)-~-cysteine] (BUC) is a novel disease-modifying antirheumatic drug (DMARD) (1).BUC is a thiol compound that differs from D-penicillamine (DP) by the presence of 2 free sulfhydryl groups. As a result, a considerable fraction of BUC can form an intramolecular disulfide (BUC-ID) that appears to have unique immunosuppressive activities. The beneficial effects of BUC in the treatment of rheumatoid arthritis (RA) have been well appreciated in several clinical trials (1-3). Thus, BUC has come to be one of the most frequently prescribed DMARDs in Japan.It has also been shown that BUC has a beneficial effect on type I1 collagen-induced arthritis in rats (4). ...

Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study

“…Bucillamine is known to suppress the function of T lymphocytes and B lymphocytes, 22 and inhibit the production of vascular endothelial growth factor (VEGF) in synovial cells. 23 On the other hand, MTX is known to suppress not only the function of lymphocytes 24,25 but also the function of neutrophils, 26 macrophages, and monocytes, 27 each of which has an important role in the pathogenesis of rheumatoid arthritis.…”

Bucillamine Induces the Synthesis of Vascular Endothelial Growth Factor Dose-Dependently in Systemic Sclerosis Fibroblasts via Nuclear Factor-κB and Simian Virus 40 Promoter Factor 1 Pathways

“…SA 96 has been characterized as an immunomodulatory agent with suppressive effects on various B and T cell functions (Hirohata and Lipsky, 1994), whereas the effects of SA 96 on the metabolism of stromal cells have not been addressed. Herein, we show that the internal disulfide SA 981, as well as SA 96 itself, is able to induce a dose-dependent increase of VEGF in cultured dermal fibroblasts.…”

Suppressive Influences of Methotrexate on the Generation of CD14 (+) Monocyte-Lineage Cells from Bone Marrow of Patients with Rheumatoid Arthritis

“…The results in the previous studies obviated the possibility that the bone marrow might be a primary target of bucillamine (8), a structural analogue of cysteine, which has a potent antirheumatic activity, presumably by inhibiting the function of B cells (25). Of note, MTX (14) as well as GST (26) has also been shown to inhibit the function of B cells.…”