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

• Published in: The Journal of pharmacology and experimental therapeutics 2003-07, Vol.306 (1), p.229-237
• Main Authors: Farrell, John, Naisbitt, Dean J., Drummond, Nicola S., Depta, Jan P.H., Vilar, F. Javier, Pirmohamed, Munir, Park, B. Kevin
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Humans; Immunity, Cellular - drug effects; Lymphocyte Activation - drug effects; Lymphocytes - drug effects; Lymphocytes - immunology; Male; Mice; Rabbits; Rats; Sulfamethoxazole - analogs & derivatives; Sulfamethoxazole - metabolism; Sulfamethoxazole - pharmacology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.050112

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.