Characterization of sulfamethoxazole and sulfamethoxazole metabolite-specific T-cell responses in animals and humans.
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.
Farrell
John
J
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, england, UK.
Naisbitt
Dean J
DJ
Drummond
Nicola S
NS
Depta
Jan P H
JP
Vilar
F Javier
FJ
Pirmohamed
Munir
M
Park
B Kevin
BK
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D013420:Sulfamethoxazole / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D013420:Sulfamethoxazole