Bucillamine suppresses human Th1 cell development by a hydrogen peroxide-independent mechanism.
OBJECTIVE
To clarify the effect of bucillamine, an antirheumatic drug related to D-penicillamine, on the development of human Th1 and Th2 cells in vitro.


METHODS
Peripheral blood mononuclear cells (PBMC) or purified CD4+ T cells were subjected to the priming culture in which cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies for 3 days and expanded for 4 days in the presence of interleukin-2. Cytokine production by the generated cells was determined on a flow cytometer using intracellular cytokine staining. The effects of bucillamine were determined by adding it for the first 3 days of the priming culture.


RESULTS
Bucillamine decreased the frequency of interferon-gamma (IFN-gamma) producing CD4+ T cells among generated CD4+ T cells after the priming culture of PBMC, although D-penicillamine did not. This effect of bucillamine was independent of hydrogen peroxide since it was not reversed by a catalase treatment. One of the bucillamine metabolites, SA981, which exerts its effects by a hydrogen peroxide-independent mechanism, decreased the frequency of IFN-gamma producing CD4+ T cells more potently than bucillamine. Bucillamine reduced the frequency of Th1 cells after the priming culture of purified CD4+CD45RO- T cells, indicating that bucillamine exerts the effect in the absence of monocytes or B cells.


CONCLUSIONS
Bucillamine directly acts on CD4+CD45RO- T cells to suppress Th1 cell development by a hydrogen peroxide-independent mechanism. This previously unknown action may explain the in vivo effect of bucillamine in the treatment of rheumatoid arthritis.
Morinobu
A
A
Department of Clinical and Laboratory Medicine, School of Medicine, Kobe University, Japan. morinobu@med.kobe-u.ac.jp
Wang
Z
Z
Kumagai
S
S
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000737:chemistry / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007371:Interferon-gamma / Q000032:analysis; D018664:Interleukin-12 / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D017493:Leukocyte Common Antigens / Q000032:analysis; D016877:Oxidants / Q000494:pharmacology*; D010396:Penicillamine / Q000737:chemistry / Q000494:pharmacology; D018417:Th1 Cells / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D007376:Interleukin-2; D016877:Oxidants; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D017493:Leukocyte Common Antigens; D010396:Penicillamine; D003545:Cysteine; C026535:bucillamine