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首页> 外文期刊>Clinical and Translational Allergy >Isoniazid-specific T-cell Responses in patients with anti-tuberculosis drug related liver injury
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Isoniazid-specific T-cell Responses in patients with anti-tuberculosis drug related liver injury

机译：抗结核药物相关肝损伤患者的异烟肼特异性T细胞反应

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BackgroundA combination of isoniazid (INH), rifampicin, pyrazinamideand/or ethambutol (anti-tuberculosis drugs, ATDs)is commonly used for the treatment of tuberculosis. Asignificant clinical problem is that drug treatment isassociated with mild elevations of liver enzymes thatoccasionally develop into severe liver injury. The culpritdrug(s) and mechanistic basis of the reaction has notbeen defined. Thus, the aims of this study were to (1)explore whether drug-responsive T-lymphocytes weredetectable in patients with ATD-related liver injury, (2)identify the drug(s) that activate T-cells and (3) characterizethe nature of the T-cell response.MethodsA lymphocyte transformation test (LTT) and IFN-ELISpotassay using ATDs and isonictinic acid (INA)-humanserum albumin (HSA) were performed on PBMCs from20 ATD-related liver injury patients. HSA was coupledwith INA using synthesized N-hydroxysuccinimide activatedester of INA. Subsequently, patients were selected toattempt to generate INH, rifampicin, pyrazinamide andethambutol-specific T-cell clones by serial dilution. Anydrug-responsive clones were then characterized in termsof function and mechanism of antigen presentation. Antigenpresent cells (APC) were (1) omitted from the assay,(2) fixed with glutaraldehyde, (3) pulsed with INH, (4)treated with MHC blocking antibodies and (5) culturedwith INH in the presence of N–acetyl-l-lysine (NAL) orother reactive metabolites-trapping agents.ResultsPBMCs from 5 patients proliferated weakly after in vitrostimulation with INH and INH-specific PBMC responseswere detectable using an IFN-ELISpot. INH, but notrifampicin, pyrazinamide or ethambutol, specific T-cellclones were generated from blood of the patients. Theclones proliferated and secreted cytokines when stimulatedwith INH alone. They responded to APC pulsed with INHfor 16h and the response was inhibited by APC fixationand with an anti-HLA class II blocking antibody. However,NAL or other reactive metabolites-trapping agents did notinhibit INH-specific proliferation.ConclusionThese studies identify INH-specific T-cells in the bloodof certain patients with ATD-related liver injury andcharacterize the nature of the drug-specific T-cellresponse. Further experiments are needed to define theway in which the drug interacts with MHC molecules tostimulate T-cells.
机译：背景异烟肼（INH），利福平，吡嗪酰胺和/或乙胺丁醇（抗结核药，ATD）的组合通常用于治疗结核病。一个重要的临床问题是药物治疗与肝酶的轻度升高相关，偶尔会发展成严重的肝损伤。尚未确定反应的罪魁祸首和机理基础。因此，本研究的目的是（1）探讨在ATD相关性肝损伤患者中是否可检测到药物反应性T淋巴细胞;（2）确定激活T细胞的药物;（3）表征其性质。方法对20例ATD相关性肝损伤患者的PBMC进行ATD和异丁酸（INA）-人血清白蛋白（HSA）的淋巴细胞转化试验（LTT）和IFN-ELIS电位测定。使用合成的INA的N-羟基琥珀酰亚胺活化酯将HSA与INA偶联。随后，选择患者尝试通过连续稀释产生INH，利福平，吡嗪酰胺和乙胺丁醇特异性T细胞克隆。然后根据抗原呈递的功能和机理表征任何药物反应性克隆。抗原存在细胞（APC）被（1）从测定中省略，（2）用戊二醛固定，（3）用INH脉冲，（4）用MHC封闭抗体处理，（5）在N–乙酰基存在下用INH培养L-赖氨酸（NAL）或其他反应性代谢产物捕获剂。结果用IFN-ELISpot可以检测到5名患者的PBMC在用INH进行体外刺激后增殖较弱，并且可以检测到INH特异性PBMC反应。从患者血液中产生INH，但不是诺福平，吡嗪酰胺或乙胺丁醇，特异性T细胞克隆。当单独用INH刺激时，克隆增殖并分泌细胞因子。他们对用INH脉冲的APC响应16h，并且该响应被APC固定和抗HLA II类阻断抗体抑制。但是，NAL或其他反应性代谢物捕获剂不能抑制INH特异性增殖。结论这些研究确定了某些ATD相关性肝损伤患者血液中的INH特异性T细胞，并表征了药物特异性T细胞反应的性质。需要进一步的实验来确定药物与MHC分子相互作用以刺激T细胞的方式。

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