期刊
TOXICOLOGICAL SCIENCES
卷 162, 期 2, 页码 713-723出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfy001
关键词
liver; HLA; drug hypersensitivity reaction; immune tolerance; idiosyncratic drug toxicity; innate immunity
类别
资金
- Japan Society for the Promotion of Science (JSPS KAKENHI) [24390037, 25670068, 15K14995, 15H04661, 16K18932, 17J03861]
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) [[2013]6075]
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [15K14995, 16K18932, 25670068, 15H04661, 24390037, 17J03861] Funding Source: KAKEN
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.
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