Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan.
Toxicol Sci. 2018 Apr 1;162(2):713-723. doi: 10.1093/toxsci/kfy001.
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-B57:01 allele. However, the underlying mechanism is unclear due to a lack of appropriate animal models. Previously, we developed HLA-B57:01 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-B57:01 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-B57:01 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.
全基因组关联研究表明，几种特有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，作为一种人类免疫缺陷病毒逆转录酶抑制剂的阿巴卡韦，仅在携带 HLA-B57:01 等位基因的患者中引起多器官毒性。然而，由于缺乏合适的动物模型，其潜在机制尚不清楚。此前，我们开发了 HLA-B57:01 转基因小鼠，并发现阿巴卡韦局部应用于耳朵会诱导局部淋巴结中 CD8+淋巴细胞的增殖。在这里，我们试图在这些小鼠中重现阿巴卡韦诱导的肝损伤。然而，单独给予 HLA-B57:01 转基因小鼠口服阿巴卡韦并未增加肝损伤标志物丙氨酸氨基转移酶的水平。考虑到固有免疫激活在小鼠肝脏中的重要性，我们用 CpG 寡脱氧核苷酸（一种 Toll 样受体 9 激动剂）加阿巴卡韦处理小鼠。这导致丙氨酸氨基转移酶明显增加，肝脏病理变化，激活的 CD8+T 细胞数量增加，以及免疫细胞仅在 HLA-B57:01 转基因小鼠中浸润。这些结果表明，CpG 寡脱氧核苷酸诱导的炎症反应和/或固有免疫激活是阿巴卡韦诱导的 HLA 介导的肝损伤所必需的，其特征是 CD8+T 细胞浸润。因此，我们开发了第一个 HLA 介导的阿巴卡韦诱导的特发性肝损伤的小鼠模型。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，从而改善药物开发并促进个性化医疗的发展。
