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TOXICOLOGY

Characterization of Sulfamethoxazole and Sulfamethoxazole Metabolite-Specific T-Cell Responses in Animals and Humans

Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, England (J.F., D.J.N., N.D., M.P., B.K.P.); Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspital, University of Bern, Bern, Switzerland (J.P.H.D.); and Department of Infectious Diseases, North Manchester General Hospital, Crumpsall, Manchester, England (F.J.V.)

Sulfamethoxazole (SMX) is associated with hypersensitivity reactions. Identification of drug-specific lymphocytes from hypersensitive patients suggests involvement of the immune system. Lymphocytes from humans recognize SMX and nitroso-SMX (SMX-NO), whereas cells from sensitized rats recognize only SMX-NO. In this investigation, we study the nature of SMX-specific T cells in four species. Male rats, mice, and rabbits were immunized with SMX (50 mg kg^–1) or SMX-NO (1 mg kg^–1). Lymphocytes and/or splenocytes were isolated and incubated with SMX, SMX-hydroxylamine or SMX-NO and proliferation were measured. Lymphocytes were also isolated from SMX-hypersensitive patients (n = 3) and drug-specific proliferation was measured. In addition, rabbits were bled fortnightly for 4 months to determine whether SMX-NO-specific T cells cross-react with SMX. To confirm that SMX-NO responses were due to covalent binding and not cross-reactivity, cells were pulsed with SMX-NO and/or coincubated with glutathione. Splenocytes from mice, rats, and rabbits proliferated when stimulated with SMX-NO, but not SMX. A 2-h pulse with SMX-NO was sufficient for proliferation, whereas cells coincubated with SMX-NO and glutathione did not proliferate. Rabbit lymphocytes proliferated in the presence of SMX-NO and SMX-hydroxylamine, but not SMX. SMX-hydroxylamine was converted to SMX-NO in culture. The SMXNO-specific response of rabbit lymphocytes was maintained for at least 4 months and the cells did not cross-react with SMX. Human lymphocytes from hypersensitive patients proliferated in the presence of SMX and both metabolites. These results highlight important differences in T-cell recognition of drug (metabolite) antigens in animals that have been sensitized against a drug metabolite and patients with hypersensitivity to the drug.

Address correspondence to: Dr. Dean J. Naisbitt, Department of Pharmacology and Therapeutics, Ashton Street Medical Bldg., The University of Liverpool, P.O. Box 147, Liverpool, L69 3BX, UK. E-mail: dnes{at}liv.ac.uk

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