The hydroxylamine of sulfamethoxazole synergizes with FK506 and cyclosporin A, inhibiting T-cell proliferation.
We previously demonstrated the capacity of the hydroxylamine metabolite of sulfamethoxazole (SMX-HA) to inhibit mitogen-induced T-cell proliferation. We studied the interaction of SMX-HA with the immuno-suppressants cyclosporin A (CsA), FK506 and rapamycin. Human peripheral blood mononuclear leukocytes were treated with SMX-HA and combined in culture with CsA or FK506 or rapamycin. The cells were stimulated with phytohaemaglutinin, and phorbol myristate acetate and proliferation was determined by cellular uptake of 3H-thymidine. Using median-effect analysis and concentration reduction index calculations to assess immunosuppressive drug interactions, we produced synergistic immunosuppression by SMX-HA/CsA and SMX-HA/FK506. Concentration reductions at the 50% inhibitory level of over 46-fold and 64-fold with CsA and FK506, respectively, were observed with 25 microM SMX-HA, and this effect was not associated with reduced cell viability. SMX-HA failed to augment the suppressive capacity of rapamycin in inhibiting mitogen-induced cellular proliferation. SMX-HA at immunosuppressive concentrations also failed to interfere with interleukin-2 mRNA transcription and interleukin-2 protein production, which suggests that signaling events proximal to cytokine production are not affected by the metabolite. Synergy between SMX-HA/FK506 and SMX-HA/CsA suggests that the mechanism(s) of action of reactive sulfonamide metabolites may occur in later stages of lymphocyte activation.
Hess
D A
DA
Department of Paediatrics, Robarts Research Institute, University of Western Ontario, London, Canada.
Bird
I A
IA
Almawi
W Y
WY
Rieder
M J
MJ
D000199:Actins / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D011090:Polyenes / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D020123:Sirolimus; D013420:Sulfamethoxazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*
D000199:Actins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011090:Polyenes; D012333:RNA, Messenger; C059873:sulfamethoxazole hydroxylamine; D016572:Cyclosporine; D013420:Sulfamethoxazole; D020123:Sirolimus; D016559:Tacrolimus