Abstract
HLA-B*13:01-positive patients in Thailand can develop frequent co-trimoxazole hypersensitivity reactions. This study aimed to characterize drug-specific T cells from three co-trimoxazole hypersensitive patients presenting with either Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms. Two of the patients carried the HLA allele of interest, namely HLA-B*13:01. Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones were generated from T cell lines of co-trimoxazole hypersensitive HLA-B*13:01-positive patients. Clones were characterized for antigen specificity and cross-reactivity with structurally related compounds by measuring proliferation and cytokine release. Surface marker expression was characterized via flow cytometry. Mechanistic studies were conducted to assess pathways of T cell activation in response to antigen stimulation. Peripheral blood mononuclear cells from all patients were stimulated to proliferate and secrete IFN-γ with nitroso sulfamethoxazole. All sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones expressed the CD4+ phenotype and strongly secreted IL-13 as well as IFN-γ, granzyme B and IL-22. No secretion of IL-17 was observed. A number of nitroso sulfamethoxazole-specific clones cross-reacted with nitroso dapsone but not sulfamethoxazole whereas sulfamethoxazole specific clones cross-reacted with nitroso sulfamethoxazole only. The nitroso sulfamethoxazole specific clones were activated in both antigen processing-dependent and -independent manner, while sulfamethoxazole activated T cell responses via direct HLA binding. Furthermore, activation of nitroso sulfamethoxazole-specific, but not sulfamethoxazole-specific, clones was blocked with glutathione. Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones from hypersensitive patients were CD4+ which suggests that HLA-B*13:01 is not directly involved in the iatrogenic disease observed in co-trimoxazole hypersensitivity patients.
Highlights
Co-trimoxazole (CTX) is a combination drug consisting of trimethoprim (TMP) and sulfamethoxazole (SMX)
We evaluated co-trimoxazole was the causative drug of Stevens–Johnson syndrome (SJS) or drug rash with eosinophilia and systemic symptoms (DRESS) using Naranjo algorithm [16], the score of the algorithm of drug causality for epidermal necrolysis (ALDEN) [17]
Several studies have shown a strong association between expression of a particular human leukocyte antigens (HLA) allele and an increased susceptibility to drug hypersensitivity reactions
Summary
Co-trimoxazole (CTX) is a combination drug consisting of trimethoprim (TMP) and sulfamethoxazole (SMX) It is commonly used for treatment of urinary tract infections due to E. coli, Klebsiella and Enterobacter spp. and suitable for gastrointestinal infections against E. coli, Shigella spp. and Salmonella typhi. Our previous case-control study demonstrated that HLA-B*13:01 is associated with cotrimoxazole-induced DRESS in Thai population, while cotrimoxazole-induced SJS/TEN was associated with HLA-B*15:02 [9]. As T cells are thought to be involved in the molecular pathogenesis of many forms of severe cutaneous adverse reactions [10,11,12], a global TCR repertoire analysis in HLA-B*15:02 positive patients with carbamazepine-induced SJS/TEN was studied and clearly demonstrated that restricted TCR usage of drug-specific T cells participated in the development of a reaction [8]. The analysis of TCR Vb repertoire of HLA-B*57:01 positive patients susceptible to abacavir hypersensitivity illustrated polyclonal TCR usages recognize the drug-HLA complex, driving the T cell activation [13,14,15]
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