The Combination of Anti-CTLA-4 and PD1-/- Mice Unmasks the Potential of Isoniazid and Nevirapine To Cause Liver Injury
The Combination of Anti-CTLA-4 and PD1-/- Mice Unmasks the Potential of Isoniazid and Nevirapine To Cause Liver Injury
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DOI：
10.1021/acs.chemrestox.5b00305
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发表时间：
2015-12-01
影响因子：
4.1
通讯作者：
Uetrecht, Jack
中科院分区：
文献类型：
--
作者：
Mak, Alastair;Uetrecht, Jack
我们的实验室最近报道了我们认为是第一个有效的特殊药物诱导肝损伤(IDILI)的动物模型，用抗CTLA-4抗体和阿莫地喹(AQ)治疗PD1-/-小鼠。PD1和CTLA-4是重要的免疫检查点受体，参与诱导免疫耐受。这种模型能够产生严重的肝脏损伤，看起来与人类的肝脏损伤非常相似。尽管这一模型被证明对AQ有效，但问题是，阻断免疫耐受是否会揭示其他药物导致IDILI的可能性。在这项研究中，我们测试了异烟肼和奈韦拉平，这两种药物在人类中都有引起IDILI的显著历史，尽管它们在导致治疗性血液水平的剂量上不会对动物造成重大伤害。这两种药物与这些免疫检查点抑制剂联合使用时，都会引起轻微但严重的延迟性肝损伤，这类似于它们可能对人类造成的轻微损伤。在该模型中，INH诱导的肝损伤与NK细胞的增加有关，而NVP诱导的肝损伤与CD8 T细胞的增加有关。尽管在该模型中，这些药物引起的肝脏损伤是轻微的，但这些结果表明，损害免疫耐受性可能是揭示药物导致IDILI的潜在可能性的一般方法，从而为药物开发提供了一种筛选工具。
Our laboratory recently reported what we believe is the first valid animal model of idiosyncratic drug-induced liver injury (IDILI) by treating PD1-/- mice with an anti-CTLA-4 antibody and amodiaquine (AQ). PD1 and CTLA-4 are important immune checkpoint receptors that are involved in inducing immune tolerance. This model was able to produce significant liver injury that looks very similar to the liver injury seen in humans. Although this model was shown to work with AQ the question becomes whether blocking immune tolerance would unmask the potential of other drugs to cause IDILI. In this study, we tested isoniazid and nevirapine, both drugs with significant histories of causing IDILI in humans even though they do not cause significant injury in animals with doses that result in therapeutic blood levels. Both drugs in combination with these immune checkpoint inhibitors caused mild but significant delayed onset liver injury, which is similar to the mild injury that they can cause in humans. INH-induced liver injury in this model was associated with an increase in NK cells, while NVP-induced liver injury was associated with a greater increase in CD8 T cells. Although the liver injury caused by these drugs in this model was mild, these results suggest that impairing immune tolerance may be a general method for unmasking the potential of drugs to cause IDILI and therefore provide a screening tool for drug development.