Dapsone and Nitroso Dapsone Activation of Naı̈ve T-Cells from Healthy Donors,Chemical Research in Toxicology

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Dapsone and Nitroso Dapsone Activation of Naı̈ve T-Cells from Healthy Donors
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2017-10-31 00:00:00 , DOI: 10.1021/acs.chemrestox.7b00263
Abdulaziz Alzahrani ₁ , Monday Ogese ₂ , Xiaoli Meng ₁ , James C. Waddington ₁ , Arun Tailor ₁ , John Farrell ₁ , James L. Maggs ₁ , Catherine Betts ₂ , B. Kevin Park ₁ , Dean Naisbitt ₁

Affiliation

Dapsone (DDS) causes hypersensitivity reactions in 0.5–3.6% of patients. Although clinical diagnosis is indicative of a hypersensitivity reaction, studies have not been performed to define whether dapsone or a metabolite activates specific T-cells. Thus, the aims of this study were to explore the immunogenicity DDS and nitroso DDS (DDS-NO) using peripheral blood mononuclear cells from healthy donors and splenocytes from mice and generate human T-cell clones to characterize mechanisms of T-cell activation. DDS-NO was synthesized from DDS-hydroxylamine and shown to bind to the thiol group of glutathione and human and mouse albumin through sulfonamide and N-hydroxyl sulphonamide adducts. Naïve T-cell priming to DDS and DDS-NO was successful in three human donors. DDS-specific CD4+ T-cell clones were stimulated to proliferate in response to drug via a MHC class II restricted direct binding interaction. Cross reactivity with DDS-NO, DDS-analogues, and sulfonamides was not observed. DDS-NO clones were CD4+ and CD8+, MHC class II and I restricted, respectively, and activated via a pathway dependent on covalent binding and antigen processing. DDS and DDS-NO-specific clones secreted a mixture of Th1 and Th2 cytokines, but not granzyme-B. Splenocytes from mice immunized with DDS-NO were stimulated to proliferate in vitro with the nitroso metabolite, but not DDS. In contrast, immunization with DDS did not activate T-cells. These data show that DDS- and DDS-NO-specific T-cell responses are readily detectable.

中文翻译：

来自健康捐献者的幼稚T细胞的氨苯砜和亚硝基苯氨苯砜活化

氨苯砜（DDS）在0.5–3.6％的患者中引起超敏反应。尽管临床诊断表明超敏反应，但尚未进行研究来确定氨苯砜或代谢物是否激活特定的T细胞。因此，本研究的目的是利用健康供体的外周血单核细胞和小鼠的脾细胞探索DDS和亚硝基DDS（DDS-NO）的免疫原性，并产生人T细胞克隆以表征T细胞活化的机制。DDS-NO由DDS-羟胺合成，并通过磺酰胺和N结合到谷胱甘肽的硫醇基以及人和小鼠白蛋白上。-羟基磺酰胺加合物。在三位人类捐赠者中，针对DDS和DDS-NO的纯朴T细胞启动成功。DDS特异性CD4 + T细胞克隆通过MHC II类限制性直接结合相互作用刺激药物增殖。未观察到与DDS-NO，DDS-类似物和磺酰胺的交叉反应性。DDS-NO克隆分别受CD4 +和CD8 +限制，MHC II类和I类受到限制，并通过依赖于共价结合和抗原加工的途径激活。DDS和DDS-NO特异性克隆分泌Th1和Th2细胞因子的混合物，但不分泌粒酶B。DDS-NO免疫小鼠的脾细胞在体外被刺激增殖与亚硝基代谢产物结合，但不与DDS结合。相反，用DDS免疫不会激活T细胞。这些数据表明，DDS和DDS-NO特异的T细胞反应很容易检测到。

更新日期：2017-10-31

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