A blinded in vitro analysis of the intrinsic immunogenicity of hepatotoxic drugs: implications for preclinical risk assessment.
A blinded in vitro analysis of the intrinsic immunogenicity of hepatotoxic drugs: implications for preclinical risk assessment.
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DOI：
10.1093/toxsci/kfad101
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发表时间：
2023-12-21
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影响因子：
--
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体外临床前药物诱导的肝损伤（DILI）风险评估主要依赖于使用肝细胞来测量细胞功能或活力的药物特异性变化。不幸的是，这并没有提供药物免疫原性和/或临床特异质反应可能性的指示。这是因为免疫DILI中的分子起始事件是药物衍生抗原与MHC蛋白和T细胞受体的相互作用。本研究利用来自未用药供体的免疫细胞、最近建立的免疫细胞共培养系统和具有和不具有DILI倾向的盲态化合物，以确定这些新方法是否优于用于预测免疫介导的DILI的已建立评估方法。研究了10种盲法测试化合物（6种具有已知的DILI倾向; 4种具有较低的DILI倾向）和5种训练化合物，其在患者中具有已知的T细胞介导的免疫反应。用4/5的训练化合物（亚硝基磺胺甲恶唑、万古霉素、Bandrowski碱和卡马西平）活化幼稚T细胞，并且用药物以剂量依赖性方式活化源自引发测定的克隆。在树突状细胞-T细胞共培养期间，具有DILI倾向的供试化合物未刺激T细胞增殖反应;然而，检测到对具有已知倾向的2种化合物（环丙沙星和红霉素）显示反应性的CD 4+克隆。使用具有较低DILI倾向的化合物时未检测到药物反应性T细胞。本研究提供了令人信服的证据，即内在药物免疫原性的评估，虽然复杂，但可以提供有关临床研究前或在患者中观察到免疫反应时某些化合物的免疫责任的有价值的信息。
In vitro preclinical drug-induced liver injury (DILI) risk assessment relies largely on the use of hepatocytes to measure drug-specific changes in cell function or viability. Unfortunately, this does not provide indications toward the immunogenicity of drugs and/or the likelihood of idiosyncratic reactions in the clinic. This is because the molecular initiating event in immune DILI is an interaction of the drug-derived antigen with MHC proteins and the T-cell receptor. This study utilized immune cells from drug-naïve donors, recently established immune cell coculture systems and blinded compounds with and without DILI liabilities to determine whether these new methods offer an improvement over established assessment methods for the prediction of immune-mediated DILI. Ten blinded test compounds (6 with known DILI liabilities; 4 with lower DILI liabilities) and 5 training compounds, with known T-cell-mediated immune reactions in patients, were investigated. Naïve T-cells were activated with 4/5 of the training compounds (nitroso sulfamethoxazole, vancomycin, Bandrowski’s base, and carbamazepine) and clones derived from the priming assays were activated with drug in a dose-dependent manner. The test compounds with DILI liabilities did not stimulate T-cell proliferative responses during dendritic cell-T-cell coculture; however, CD4+ clones displaying reactivity were detected toward 2 compounds (ciprofloxacin and erythromycin) with known liabilities. Drug-responsive T-cells were not detected with the compounds with lower DILI liabilities. This study provides compelling evidence that assessment of intrinsic drug immunogenicity, although complex, can provide valuable information regarding immune liabilities of some compounds prior to clinical studies or when immune reactions are observed in patients.
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DOI：
10.1002/hep.31538
发表时间：
2021-06
期刊：
Hepatology (Baltimore, Md.)
影响因子：
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作者：
Hoofnagle JH;Bonkovsky HL;Phillips EJ;Li YJ;Ahmad J;Barnhart H;Durazo F;Fontana RJ;Gu J;Khan I;Kleiner DE;Koh C;Rockey DC;Seeff LB;Serrano J;Stolz A;Tillmann HL;Vuppalanchi R;Navarro VJ;Drug-Induced Liver Injury Network
通讯作者：
Drug-Induced Liver Injury Network
影响因子：
158.5
作者：
Chen, Pei;Lin, Juei-Jueng;Shen, Chen-Yang
通讯作者：
Shen, Chen-Yang
DOI：
10.1084/jem.147.6.1671
发表时间：
1978-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Seldin MF;Rich RR
通讯作者：
Rich RR
影响因子：
3.8
作者：
Faulkner, Lee;Martinsson, Klara;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
4.1
作者：
Kato, Ryuji;Uetrecht, Jack
通讯作者：
Uetrecht, Jack