TY - JOUR T1 - The Hydroxylamine of Sulfamethoxazole Synergizes with FK506 and Cyclosporin A, Inhibiting T-Cell Proliferation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 540 LP - 548 VL - 281 IS - 1 AU - David A. Hess AU - Ingrid A. Bird AU - Wassim Y. Almawi AU - Michael J. Rieder Y1 - 1997/04/01 UR - http://jpet.aspetjournals.org/content/281/1/540.abstract N2 - 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 of3H-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 μM 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. The American Society for Pharmacology and Experimental Therapeutics ER -