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首页> 外文期刊>Clinical and Translational Allergy >Identification of susceptible HLA class II co-amoxiclav genotypes based on the analysis of drug-specific T-cells from patients with liver injury
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Identification of susceptible HLA class II co-amoxiclav genotypes based on the analysis of drug-specific T-cells from patients with liver injury

机译：基于肝损伤患者的药物特异性T细胞分析，确定易感性HLA II类共阿莫西夫拉基因型

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Drug-induced liver injury (DILI) is a major concern forpublic health. Several forms of DILI are associated withthe expression of specific MHC genes suggesting thatthe adaptive immune system is involved in the diseasepathogenesis. We have identified drug-responsiveT-cells in patients with flucloxacillin induced DILI andshown that the drug antigen is presented to T-cells inthe context of the HLA risk allele (HLA-B*5701). Thecombination of amoxicillin and clavulanic acid (coamoxiclav)is one of the most frequently prescribeddrugs. Occasionally, human exposure is associated withDILI. Individual susceptibility can be influenced by HLAgenotypes (e.g. DRB1*1501 risk; DRB1*07:01 risk) andwe have recently characterized drug-specific T-cells inpatients with co-amoxiclav-induced DILI. The objectiveof this study was to use amoxicillin-specific CD4+ T-cellclones from 2 DILI patients to investigate the mechanismsof drug antigen presentation and to identifysusceptible HLA class II genotypes based on analysis ofdrug specific T-cell responses.MethodAntigen presenting cells (APC) expressing different HLAalleles generated from our HLA-typed PBMC cell bankwere used to investigate the latter. EBV-transformed B-celllines from 15 donors expressing HLA alleles of interestwere generated and used as APC. To characterizemechanism(s) of T-cell activation, APC were (1) omittedfrom the assay, (2) pulsed with amoxicillin for 1-16h and(3) treated with MHC blocking antibodies.ResultsThe clones showed a strong proliferative response andIFN secretion following exposure to amoxicillin andautologous APC. Activation of the clones was alsoobserved with APC pulsed with amoxicillin for 16h. Theresponse was strongly inhibited with an anti-HLA classII antibody. More detailed analysis using HLA-DR, -DPand -DQ antibodies revealed that the response wasHLA-DR restricted. Allogeneic APC were then used todefine HLA-DR alleles involved in the drug-specificresponse. Clones were activated with amoxicillin andallogeneic APC expressing a range of DRB1 allelesincluding 03:01, 04:01, 13:01 and 15:01. In contrast,amoxicillin did not activate the clones with APC expressingHLA-DRB1*01:01 and 07:01.ConclusionThese findings characterizing HLA-restricted amoxicillinspecificT-cell responses agree with recent genome-wideassociation studies which identify specific HLA-DRB1alleles as risk factors that influence susceptibility toco-amoxiclav-induced liver injury.
机译：药物性肝损伤（DILI）是公共卫生的主要关注点。几种形式的DILI与特定MHC基因的表达有关，表明适应性免疫系统参与了疾病的发病机理。我们已经在氟氯西林诱导的DILI患者中鉴定了药物反应性T细胞，并显示在HLA风险等位基因（HLA-B * 5701）的情况下，药物抗原呈递给T细胞。阿莫西林和克拉维酸（coamoxiclav）的组合是最常用的处方药之一。有时候，人体暴露与DILI有关。个体易感性可能会受到HLA基因型的影响（例如DRB1 * 1501风险; DRB1 * 07：01风险），并且我们最近对患有coamoxiclav诱导的DILI患者的药物特异性T细胞进行了表征。这项研究的目的是使用来自2名DILI患者的阿莫西林特异性CD4 + T细胞克隆来研究药物抗原呈递的机制，并在分析药物特异性T细胞反应的基础上鉴定出易感的HLA II类基因型。方法抗原呈递细胞（APC）表达不同从我们的HLA型PBMC细胞库生成的HLA等位基因用于研究后者。来自15个表达感兴趣的HLA等位基因的供体的EBV转化的B细胞系被产生并用作APC。为了表征T细胞活化的机制，将APC从以下步骤中剔除：（1）省略了APC;（2）用阿莫西林脉冲1-16h;（3）用MHC阻断抗体处理。结果接触阿莫西林和自体APC。还用阿莫西林脉冲16小时的APC观察了克隆的活化。抗HLA II类抗体强烈抑制了反应。使用HLA-DR，-DP和-DQ抗体进行的更详细的分析显示，应答受HLA-DR限制。然后使用同种异体APC定义参与药物特异性反应的HLA-DR等位基因。用表达一系列DRB1等位基因的阿莫西林和异源APC激活克隆，包括03：01、04：01、13：01和15:01。相比之下，阿莫西林未激活表达HLA-DRB1 * 01：01和07:01的APC的克隆。结论这些表征HLA限制的阿莫西林特异性T细胞反应的特征与最近的全基因组关联研究一致，该研究确定了特定的HLA-DRB1等位基因为危险因素，影响易莫昔洛韦引起的肝损伤的易感性。

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