An Animal Model of Abacavir-Induced HLA-Mediated Liver Injury
An Animal Model of Abacavir-Induced HLA-Mediated Liver Injury
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DOI：
10.1093/toxsci/kfy001
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发表时间：
2018-04
影响因子：
3.8
通讯作者：
B. Song;Shigeki Aoki;Cong Liu;Takeshi Susukida;Kousei Ito
中科院分区：
文献类型：
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作者：
B. Song;Shigeki Aoki;Cong Liu;Takeshi Susukida;Kousei Ito
全基因组关联研究表明，一些特殊的药物不良反应与特定的人类白细胞抗原（HLA）等位基因高度相关。例如，人类免疫缺陷病毒逆转录酶抑制剂阿巴卡韦仅在携带HLA-B*57:01等位基因的患者中诱导多器官毒性。然而，由于缺乏适当的动物模型，其潜在机制尚不清楚。在此之前，我们开发了HLA-B*57:01转基因小鼠，发现阿巴卡韦局部应用于耳朵可诱导局部淋巴结CD8+淋巴细胞增殖。在这里，我们试图在这些小鼠中重现阿巴韦诱导的肝损伤。然而，给HLA-B*57:01转基因小鼠单独口服阿巴卡韦并没有增加肝损伤标志物丙氨酸转氨酶的水平。考虑到小鼠肝脏先天免疫激活的重要性，我们用CpG寡脱氧核苷酸（一种toll样受体9激动剂）加阿巴卡韦治疗小鼠。结果表明，在HLA-B*57:01转基因小鼠中，丙氨酸转氨酶显著升高，肝脏病理改变，CD8+ T细胞活化数量增加，免疫细胞独占组织浸润。这些结果表明，CpG低聚脱氧核苷酸诱导的炎症反应和/或先天免疫激活对于以CD8+ T细胞浸润为特征的阿巴卡韦诱导的hla介导的肝损伤是必要的。因此，我们建立了第一个hla介导的阿巴卡韦诱导的特异性肝损伤小鼠模型。进一步的研究将表明，所提出的HLA介导的肝损伤模型可以应用于其他药物和HLA类型的组合，从而改善药物开发，促进个性化医疗的发展。
Genome-wide association studies indicate that several idiosyncratic adverse drug reactions are highly associated with specific human leukocyte antigen (HLA) alleles. For instance, abacavir, a human immunodeficiency virus reverse transcriptase inhibitor, induces multiorgan toxicity exclusively in patients carrying the HLA-B*57:01 allele. However, the underlying mechanism is unclear due to a lack of appropriate animal models. Previously, we developed HLA-B*57:01 transgenic mice and found that topical application of abacavir to the ears induced proliferation of CD8+ lymphocytes in local lymph nodes. Here, we attempted to reproduce abacavir-induced liver injury in these mice. However, oral administration of abacavir alone to HLA-B*57:01 transgenic mice did not increase levels of the liver injury marker alanine aminotransferase. Considering the importance of innate immune activation in mouse liver, we treated mice with CpG oligodeoxynucleotide, a toll-like receptor 9 agonist, plus abacavir. This resulted in a marked increase in alanine aminotransferase, pathological changes in liver, increased numbers of activated CD8+ T cells, and tissue infiltration by immune cells exclusively in HLA-B*57:01 transgenic mice. These results indicate that CpG oligodeoxynucleotide-induced inflammatory reactions and/or innate immune activation are necessary for abacavir-induced HLA-mediated liver injury characterized by infiltration of CD8+ T cells. Thus, we developed the first mouse model of HLA-mediated abacavir-induced idiosyncratic liver injury. Further investigation will show that the proposed HLA-mediated liver injury model can be applied to other combinations of drugs and HLA types, thereby improving drug development and contributing to the development of personalized medicine.