PMID- 29319822
OWN - NLM
STAT- MEDLINE
DCOM- 20190225
LR  - 20190225
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 162
IP  - 2
DP  - 2018 Apr 1
TI  - An Animal Model of Abacavir-Induced HLA-Mediated Liver Injury.
PG  - 713-723
LID - 10.1093/toxsci/kfy001 [doi]
AB  - 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.
FAU - Song, Binbin
AU  - Song B
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chuo-ku, Chiba 260-8675, Japan.
FAU - Aoki, Shigeki
AU  - Aoki S
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chuo-ku, Chiba 260-8675, Japan.
FAU - Liu, Cong
AU  - Liu C
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chuo-ku, Chiba 260-8675, Japan.
FAU - Susukida, Takeshi
AU  - Susukida T
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chuo-ku, Chiba 260-8675, Japan.
FAU - Ito, Kousei
AU  - Ito K
AD  - Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba 
      University, Chuo-ku, Chiba 260-8675, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (CpG ODN 1826)
RN  - 0 (Dideoxynucleosides)
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B*57:01 antigen)
RN  - 0 (Oligodeoxyribonucleotides)
RN  - 0 (Reverse Transcriptase Inhibitors)
RN  - 0 (Tlr9 protein, mouse)
RN  - 0 (Toll-Like Receptor 9)
RN  - EC 2.6.1.2 (Alanine Transaminase)
RN  - WR2TIP26VS (abacavir)
SB  - IM
MH  - Alanine Transaminase/blood
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/drug effects/immunology
MH  - Chemical and Drug Induced Liver Injury/etiology/genetics/*immunology/pathology
MH  - Dideoxynucleosides/*toxicity
MH  - *Disease Models, Animal
MH  - HLA-B Antigens/*genetics
MH  - Hepatocytes/drug effects/immunology/pathology
MH  - Immunity, Innate/drug effects/genetics
MH  - Liver/*drug effects/immunology/pathology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Oligodeoxyribonucleotides/pharmacology
MH  - Reverse Transcriptase Inhibitors/*toxicity
MH  - Toll-Like Receptor 9/agonists
EDAT- 2018/01/11 06:00
MHDA- 2019/02/26 06:00
CRDT- 2018/01/11 06:00
PHST- 2018/01/11 06:00 [pubmed]
PHST- 2019/02/26 06:00 [medline]
PHST- 2018/01/11 06:00 [entrez]
AID - 4793110 [pii]
AID - 10.1093/toxsci/kfy001 [doi]
PST - ppublish
SO  - Toxicol Sci. 2018 Apr 1;162(2):713-723. doi: 10.1093/toxsci/kfy001.