Immunosuppression by the disease modifying antirheumatic drug bucillamine: inhibition of human T lymphocyte function by bucillamine and its metabolites.
OBJECTIVE
Bucillamine: N-(2-mercapto-2-methyl-propanoyl)-L-cysteine has recently been suggested to be effective in the treatment of rheumatoid arthritis (RA). The molecular structure of this compound is similar to that of D-penicillamine, except that bucillamine has 2 free sulfhydryl groups in its structure whereas D-penicillamine has only one. The goal of our studies was to determine whether bucillamine exerted immunosuppressive effects in vitro.


METHODS
The effect of bucillamine and its metabolites on mitogen induced proliferation and IL-2 production by human T cells was examined.


RESULTS
Bucillamine, and its metabolites SA 679, and SA 981 inhibited mitogen induced T cell responses. The inhibitory effect of bucillamine and SA 679, in which one sulfhydryl group is S-methylated, was markedly augmented in the presence of CuSO4, and the effect was completely prevented by the addition of catalase. The capacity of SA 981, the internal disulfide of bucillamine, to inhibit T lymphocyte responses was not dependent on the presence of CuSO4. SA 672, in which both sulfhydryl groups are S-methylated, did not inhibit T cell proliferation.


CONCLUSIONS
Our results suggest that bucillamine has 2 distinct inhibitory effects on T cell function. One is the ability to generate H2O2 in the presence of CuSO4 and is attributable to its free thiol groups. The other is related to a separate inhibitory mechanism, that is not dependent on CuSO4 or the reduced thiol groups. These 2 immunosuppressive effects may account for the potency of bucillamine in suppressing rheumatoid inflammation.
Hashimoto
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Harold C. Simmons Arthritis Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
Lipsky
P E
PE
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002374:Catalase / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D015394:Molecular Structure; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D007376:Interleukin-2; C045920:N-2-methyl-2-(methylthio)propanoyl-L-cysteine; D002374:Catalase; D003545:Cysteine; C026535:bucillamine