An Animal Model of Abacavir-Induced HLA-Mediated Liver Injury

作者：Song Binbin; Aoki Shigeki; Liu Cong; Susukida Takeshi; Ito Kousei

来源：Toxicological Sciences, 2018, 162(2): 713-723.

DOI：10.1093/toxsci/kfy001

• liver
• HLA
• drug hypersensitivity reaction
• immune tolerance
• idiosyncratic drug toxicity
• innate immunity

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, inducesmultiorgan toxicity exclusively in patients carrying the HLA-B* 57: 01 allele. However, the underlyingmechanism is unclear due to a lack of appropriate animal models. Previously, we developed HLA-B* 57: 01 transgenicmice and found that topical application of abacavir to the ears induced proliferation of CD8thorn lymphocytes in local lymph nodes. Here, we attempted to reproduce abacavir-induced liver injury in thesemice. 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 treatedmice with CpG oligodeoxynucleotide, a toll-like receptor 9 agonist, plus abacavir. This resulted in amarked increase in alanine aminotransferase, pathological changes in liver, increased numbers of activated CD8thorn T cells, and tissue infiltration by immune cells exclusively in HLA-B* 57: 01 transgenicmice. 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 CD8thorn 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.

• 出版日期2018-4