Treatment of PD-1-/- Mice With Amodiaquine and Anti-CTLA4 Leads to Liver Injury Similar to Idiosyncratic Liver Injury in Patients
Treatment of PD-1-/- Mice With Amodiaquine and Anti-CTLA4 Leads to Liver Injury Similar to Idiosyncratic Liver Injury in Patients
复制标题
DOI：
10.1002/hep.27549
复制
发表时间：
2015-04-01
期刊：
影响因子：
13.5
通讯作者：
Uetrecht, Jack
中科院分区：
文献类型：
--
作者：
Metushi, Imir G.;Hayes, M. Anthony;Uetrecht, Jack
特异质药物性肝损伤（IDILI）的机制仍然知之甚少，在很大程度上是因为缺乏有效的动物模型。最近，我们报道了一种动物模型，其中用阿莫地喹（AQ）治疗雌性C57 BL/6小鼠导致轻度肝损伤，尽管继续治疗，但发病和消退延迟。这种适应是由可导致肝功能衰竭的药物引起的IDILI的常见结果。我们假设大多数IDILI是免疫介导的，适应代表免疫耐受。在这项研究中，我们发现AQ治疗免疫耐受受损的Cbl-b（-/-）和PD-1（-/-）小鼠，导致轻微的损伤。C57 BL/6与AQ和抗CTLA 4的共处理也导致ALT比单独用AQ处理更大的增加;然而，这些小鼠也具有表达PD-1和CTLA 4的T调节（Treg）细胞和T辅助细胞的增加。这些细胞的增加意味着免疫耐受的诱导，尽管继续治疗，这些小鼠中的丙氨酸氨基转移酶（ALT）活性恢复正常。PD-1（-/-）小鼠与抗CTLA 4抗体和AQ的共同治疗导致ALT（200-300 U/L）的最大增加，以及以淋巴细胞门静脉浸润为特征的坏死性炎症反应和界面性肝炎。淋巴细胞浸润包括T和B细胞，CD 8（+）T细胞产生穿孔素和颗粒酶。此外，抗CTLA 4抗体和AQ共处理的PD-1（-/-）小鼠的ALT活性没有恢复正常，因为它在其他小鼠中恢复正常。结论：我们在这里报告了第一个IDILI的动物模型，它类似于在人类中发生的IDILI，它是通过抑制免疫耐受来实现的。（肝病学2015;61：1332-1342）
The mechanism of idiosyncratic drug-induced liver injury (IDILI) remains poorly understood, to a large degree because of the lack of a valid animal model. Recently, we reported an animal model in which treatment of female C57BL/6 mice with amodiaquine (AQ) resulted in mild liver injury with a delayed onset and resolution despite continued treatment. Such adaptation is a common outcome in the IDILI caused by drugs that can cause liver failure. We had hypothesized that most IDILI is immune-mediated and adaptation represents immune tolerance. In this study we found that AQ treatment of Cbl-b(-/-) and PD-1(-/-) mice, which have impaired immune tolerance, resulted in a slightly greater injury. Cotreatment of C57BL/6 with AQ and anti-CTLA4 also resulted in a greater increase in ALT than treatment with AQ alone; however, these mice also had an increase in T regulatory (Treg) cells and T helper cells expressing PD-1 and CTLA4. The increase in these cells implies the induction of immune tolerance, and the alanine aminotransferase (ALT) activity in these mice returned to normal despite continued treatment. Cotreatment of PD-1(-/-) mice with anti-CTLA4 antibody and AQ resulted in the greatest increase in ALT (200-300 U/L), and necroinflammatory responses characterized by portal infiltration of lymphocytes with interface hepatitis. The lymphocyte infiltration included T and B cells, and the CD8(+) T cells produced perforin and granzyme. In addition, the ALT activity in PD-1(-/-) mice cotreated with anti-CTLA4 antibody and AQ did not return to normal, as it had in other mice. Conclusion: We report here the first animal model of IDILI that is similar to the IDILI that occurs in humans, and it was accomplished by inhibiting immune tolerance. (Hepatology 2015;61:1332-1342)