In vitro and in vivo inhibition of activation induced T cell apoptosis by bucillamine.
OBJECTIVE
To investigate the mechanism of autoimmune phenomena, occasionally seen in patients with rheumatoid arthritis treated with bucillamine (BUC) and D-penicillamine (D-Pen), by evaluating their effects on apoptosis of T cells induced by T cell receptor activation or dexamethasone.


METHODS
In vitro apoptosis was induced in a T cell hybridoma (SSP3.7) and a B cell line (WEHI 231) by activation of respective receptors or dexamethasone, in the presence or absence of BUC or D-Pen. In vivo apoptosis was induced in BALB/c mice by staphylococcal enterotoxin B (SEB), with or without BUC or D-Pen, and thymocytes were examined for it by FACS.


RESULTS
Stimulation with anti-CD3 and dexamethasone induced apoptosis in 72% and 71% of SSP3.7 cells, respectively. However, only 16% of SSP3.7 cells became apoptotic by anti-CD3 when BUC was added to the culture media. By contrast, 80% of SSP3.7 cells became apoptotic when stimulated by dexamethasone, even in the presence of BUC. BUC did not affect apoptosis of WEHI 231 cells induced by anti-IgM. Although SA981 (a metabolite of BUC) inhibited apoptosis of SSP3.7 cells induced by anti-CD3, D-Pen did not. BUC, SA981, or D-Pen did not significantly influence the level of interleukin 2 secretion stimulated by anti-CD3. In contrast, both BUC and D-Pen inhibited apoptosis of Vbeta8+ thymocytes induced in vivo by SEB superantigen. Neither BUC nor D-Pen significantly changed the number of CD4+CD8+ thymocytes in BALB/c mice injected with dexamethasone.


CONCLUSIONS
BUC decreased, while D-Pen did not, the apoptosis of T cells stimulated by anti-CD3 in vitro, although they both inhibited the deletion of immature thymocytes reactive with SEB in vivo. This may explain autoimmune phenomena sometimes seen during the treatment of rheumatic patients with these drugs.
Okazaki
H
H
Division of Clinical Immunology, Jichi Medical School, Tochigi-Ken, Japan.
Sato
H
H
Kamimura
T
T
Hirata
D
D
Iwamoto
M
M
Yoshio
T
T
Mimori
A
A
Masuyama
J I
JI
Kano
S
S
Minota
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000906:Antibodies / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology; D006825:Hybridomas; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010396:Penicillamine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018089:Superantigens / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D018501:Antirheumatic Agents; D017252:CD3 Complex; D004768:Enterotoxins; D005938:Glucocorticoids; D007376:Interleukin-2; D017382:Reactive Oxygen Species; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; C045920:N-2-methyl-2-(methylthio)propanoyl-L-cysteine; D003907:Dexamethasone; D010396:Penicillamine; D003545:Cysteine; C026535:bucillamine