Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Department of Clinical Chemistry, Faculty of Medical Technology, Huachiew Chalermprakiet University, Samut Prakan, Thailand.
Front Immunol. 2021 Apr 29;12:658593. doi: 10.3389/fimmu.2021.658593. eCollection 2021.
-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 . Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones were generated from T cell lines of co-trimoxazole hypersensitive -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 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 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 is not directly involved in the iatrogenic disease observed in co-trimoxazole hypersensitivity patients.
在泰国，阳性患者可能会频繁出现复方新诺明过敏反应。本研究旨在从出现史蒂文斯-约翰逊综合征或药物反应伴嗜酸性粒细胞增多和全身症状的 3 名复方新诺明过敏患者中鉴定对药物具有特异性的 T 细胞。其中 2 名患者携带感兴趣的 HLA 等位基因，即。从复方新诺明过敏阳性患者的 T 细胞系中生成了磺胺甲噁唑和亚硝基磺胺甲噁唑特异性 T 细胞克隆。通过测量增殖和细胞因子释放来鉴定克隆的抗原特异性和与结构相关化合物的交叉反应性。通过流式细胞术鉴定表面标志物表达。进行了机制研究以评估针对抗原刺激的 T 细胞激活途径。用亚硝基磺胺甲噁唑刺激所有患者的外周血单核细胞增殖并分泌 IFN-γ。所有磺胺甲噁唑和亚硝基磺胺甲噁唑特异性 T 细胞克隆均表达 CD4+表型，并强烈分泌 IL-13 以及 IFN-γ、颗粒酶 B 和 IL-22。未观察到 IL-17 的分泌。一些亚硝基磺胺甲噁唑特异性克隆与亚硝基达普司酮交叉反应，但与磺胺甲噁唑不交叉反应，而磺胺甲噁唑特异性克隆仅与亚硝基磺胺甲噁唑交叉反应。亚硝基磺胺甲噁唑特异性克隆以抗原处理依赖和非依赖的方式被激活，而磺胺甲噁唑通过直接 HLA 结合激活 T 细胞反应。此外，用谷胱甘肽阻断了亚硝基磺胺甲噁唑特异性但非磺胺甲噁唑特异性克隆的激活。来自过敏患者的磺胺甲噁唑和亚硝基磺胺甲噁唑特异性 T 细胞克隆为 CD4+，这表明 HLA-DRB1*15:01 并非直接参与复方新诺明过敏患者中观察到的医源性疾病。
