Induction of delayed-type hypersensitivity to sulfamethoxazole in mice: role of metabolites

Choquet-Kastylevsky, Geneviève; Santolaria, N.; Tédone, R.; Aujoulat, Michel; Descotes, Jacques

doi:10.1016/s0378-4274(00)00313-1

Cited by 19 publications

(11 citation statements)

References 25 publications

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“…Chemical (thiol-depleting agents) and immunological (adjuvants) modulation, before SMX administration, confirmed that oxidative metabolism of SMX was required to stimulate a primary drug antigen-specific immune response in vivo. These observations are consistent with the demonstration of SMX metabolite-specific, but not SMX-specific, delayed-type hypersensitivity in mice (Choquet-Kastylevsky et al, 2001) and the original hapten hypothesis.…”

supporting

confidence: 91%

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

Farrell

Naisbitt²,

Drummond³

et al. 2003

J Pharmacol Exp Ther

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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 SMXspecific T cells in four species. Male rats, mice, and rabbits were immunized with SMX (50 mg kg Ϫ1 ) or SMX-NO (1 mg kg Ϫ1 ). 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 ϭ 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 SMX-NO-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.

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supporting

confidence: 91%

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

Farrell

Naisbitt²,

Drummond³

et al. 2003

J Pharmacol Exp Ther

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“…In rodent models, topical and systemic exposure to nitroso SMX primes naive CD4+ and CD8+ T cells. The T-cell response is dependent on protein processing, and liberated peptide antigens are presented to specific T-cell receptors in the context of MHC molecules (Choquet-Kastylevsky et al, 2001;Naisbitt et al, 2001Naisbitt et al, , 2002Farrell et al, 2003;Hopkins et al, 2005;Castrejon et al, 2010b). In contrast, administration of SMX does not activate immune cells.…”

Section: The Antigenicity and Immunogenicity Of Drugs That Acquirementioning

confidence: 99%

Idiosyncratic Adverse Drug Reactions: Current Concepts

2013

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“…[18][19][20][21][22][23][24] SMX-NO is a potent immunogen in experimental models, and intracellular generation in dendritic cells is associated with costimulatory signaling. 10,19,20,[25][26][27][28] SMX-NO activates T lymphocytes from 90% of drug-naive volunteers after 14 to 35 days of in vitro culture. Furthermore, T cells from SMX-NO-immunized animals proliferate in the presence of SMX-NO-modified protein.…”

mentioning

confidence: 99%