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

Although cutaneous adverse drug reactions (ADRs) are relatively frequent an d potentially severe, their mechanisms are poorly understood and no validat ed predictive experimental model is available. Sulfamethoxazole (SMX) is co mmonly used to treat infections in HIV-positive patients and severe cutaneo us ADRs have been described. This study was undertaken to test whether sens itization to SMX could be achieved in mice using a combination of in vivo a nd in vitro endpoints. No delayed-type hypersensitivity (DTH) response coul d be evidenced following SMX injection in the back and subsequent challenge into the footpad or onto the ear. Pretreatment with the enzymatic inducers phenobarbitone and betanaphtoflavone, or depletion in CD4(+) T-lymphocytes were not successful either. In contrast, the injection of SMX/S9 mix in th e back and challenge with SMX/S9 mix induced a significant increase in foot pad thickness. A significant proliferation of spleen cells from SMX- or SMX /S9 mix-treated mice was evidenced following incubation with SMX/S9 mix, bu t not SMX alone. This study provides indirect evidence that SMX metabolites are involved and confirms previous in vitro results obtained with lymphocy tes from patients with a history of SMX-induced ADRs cultured with murine m icrosomes. Further investigations using other drugs known to induce similar ADRs are warranted to establish the predictive value of this murine model. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.