Deciphering Adverse Drug Reactions: In Vitro Priming and Characterization of Vancomycin-Specific T Cells From Healthy Donors Expressing HLA-A*32:01.
Deciphering Adverse Drug Reactions: In Vitro Priming and Characterization of Vancomycin-Specific T Cells From Healthy Donors Expressing HLA-A*32:01.
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DOI：
10.1093/toxsci/kfab084
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发表时间：
2021-08-30
期刊：
影响因子：
--
通讯作者：
Naisbitt DJ
中科院分区：
文献类型：
--
作者：
Ogese MO;Lister A;Gardner J;Meng X;Alfirevic A;Pirmohamed M;Park BK;Naisbitt DJ
伴有全身症状的嗜酸性粒细胞增多性药疹（DRESS）是与糖肽类抗生素万古霉素使用相关的严重不良事件。万古霉素诱导的药物皮疹伴嗜酸性粒细胞增多伴全身症状与人类白细胞抗原（HLA）-A*32：01的表达相关，表明药物与该HLA相互作用以激活CD 8 + T细胞。本研究的目的是利用来自健康供体的外周血单个核细胞：（1）研究HLA-A*32：01的表达是否对万古霉素初始化T细胞至关重要;（2）产生T细胞克隆（TCC），以确定万古霉素是否仅激活CD 8 + T细胞，并确定细胞表型、药物呈递途径和交叉反应性。树突状细胞与幼稚T细胞和万古霉素一起培养2周。第14天，用万古霉素重新刺激细胞，并通过[3 H]-胸苷掺入来评估T细胞增殖。万古霉素特异性TCC通过连续稀释和重复促分裂原刺激产生。来自HLA-A*02：01阳性和阴性供体的幼稚T细胞用万古霉素活化;然而，在表达HLA-A*32：01的供体中诱导的应答的强度显著更强。来自HLA-A*32：01+供体的万古霉素应答性CD 4+和CD 8 + TCC表达高水平的CXCR 3和CCR 4，并分泌IFN-γ、IL-13和细胞溶解分子。CD 8 + TCC的活化是HLA I类限制性的，并依赖于直接的万古霉素HLA结合相互作用，不需要处理。几种TCC显示与替考拉宁和达托霉素的交叉反应性。综上所述，本研究提供的证据表明，万古霉素通过直接的药理学结合相互作用引发来自表达HLA-A*32：01的健康供体的幼稚T细胞。CD 8 + TCC与替考拉宁的交叉反应性为万古霉素超敏患者中观察到的替考拉宁反应提供了解释。
Drug rash with eosinophilia with systemic symptoms (DRESS) is a serious adverse event associated with use of the glycopeptide antibiotic vancomycin. Vancomycin-induced drug rash with eosinophilia with systemic symptoms is associated with the expression of human leukocyte antigen (HLA)-A*32:01, suggesting that the drug interacts with this HLA to activate CD8+ T cells. The purpose of this study was to utilize peripheral blood mononuclear cell from healthy donors to: (1) investigate whether expression of HLA-A*32:01 is critical for the priming naïve of T cells with vancomycin and (2) generate T-cell clones (TCC) to determine whether vancomycin exclusively activates CD8+ T cells and to define cellular phenotype, pathways of drug presentation and cross-reactivity. Dendritic cells were cultured with naïve T cells and vancomycin for 2 weeks. On day 14, cells were restimulated with vancomycin and T-cell proliferation was assessed by [3H]-thymidine incorporation. Vancomycin-specific TCC were generated by serial dilution and repetitive mitogen stimulation. Naïve T cells from HLA-A*02:01 positive and negative donors were activated with vancomycin; however the strength of the induced response was significantly stronger in donors expressing HLA-A*32:01. Vancomycin-responsive CD4+ and CD8+ TCC from HLA-A*32:01+ donors expressed high levels of CXCR3 and CCR4, and secreted IFN‐γ, IL-13, and cytolytic molecules. Activation of CD8+ TCC was HLA class I-restricted and dependent on a direct vancomycin HLA binding interaction with no requirement for processing. Several TCC displayed cross-reactivity with teicoplanin and daptomycin. To conclude, this study provides evidence that vancomycin primes naïve T cells from healthy donors expressing HLA-A*32:01 through a direct pharmacological binding interaction. Cross-reactivity of CD8+ TCC with teicoplanin provides an explanation for the teicoplanin reactions observed in vancomycin hypersensitive patients.
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DOI：
10.1097/qad.0b013e328355fe8f
发表时间：
2012-07-17
期刊：
AIDS (London, England)
影响因子：
--
作者：
Norcross MA;Luo S;Lu L;Boyne MT;Gomarteli M;Rennels AD;Woodcock J;Margulies DH;McMurtrey C;Vernon S;Hildebrand WH;Buchli R
通讯作者：
Buchli R
影响因子：
158.5
作者：
Mallal, Simon;Phillips, Elizabeth;Benbow, Alastair
通讯作者：
Benbow, Alastair
影响因子：
15.9
作者：
Zanni, MP;von Greyerz, S;Pichler, WJ
通讯作者：
Pichler, WJ
影响因子：
3.7
作者：
Groom JR;Luster AD
通讯作者：
Luster AD
影响因子：
5.3
作者：
Blaskovich MAT;Hansford KA;Butler MS;Jia Z;Mark AE;Cooper MA
通讯作者：
Cooper MA