Archives of Toxicology

, Volume 92, Issue 3, pp 1177–1188 | Cite as

Evaluation of immune-mediated idiosyncratic drug toxicity using chimeric HLA transgenic mice

  • Takeshi Susukida
  • Shigeki Aoki
  • Kotaro Kogo
  • Sota Fujimori
  • Binbin Song
  • Cong Liu
  • Shuichi Sekine
  • Kousei Ito
Immunotoxicology
  • 322 Downloads

Abstract

Immune-mediated idiosyncratic drug toxicity (IDT) is a rare adverse drug reaction, potentially resulting in death. Although genome-wide association studies suggest that the occurrence of immune-mediated IDT is strongly associated with specific human leukocyte antigen (HLA) allotypes, these associations have not yet been prospectively demonstrated. In this study, we focused on HLA-B*57:01 and abacavir (ABC)-induced immune-mediated IDT, and constructed transgenic mice carrying chimeric HLA-B*57:01 (B*57:01-Tg) to determine if this in vivo model may be useful for evaluating immune-mediated IDT. Local lymph node assay (LLNA) results demonstrated that percentages of BrdU+, IL-2+, and IFN-γ+ in CD8+ T cells of ABC (50 mg/kg/day)-applied B*57:01-Tg mice were significantly higher than those in littermates (LMs), resulting in the infiltration of inflammatory cells into the ear. These immune responses were not observed in B*57:03-Tg mice (negative control). Furthermore, oral administration of 1% (v/v) ABC significantly increased the percentage of CD44highCD62Llow CD8+ memory T cells in lymph nodes and spleen derived from B*57:01-Tg mice, but not in those from B*57:03-Tg mice and LMs. These results suggest that B*57:01-Tg mice potentially enable the reproduction and evaluation of HLA-B*57:01 and ABC-induced immune-mediated IDT.

Keywords

Idiosyncratic drug toxicity Immunotoxicology Human leucocyte antigen In vivo model Abacavir 

Abbreviations

ABC

Abacavir

BSA

Bovine serum albumin

BrdU

Bromodeoxyuridine

CTLA-4

Cytotoxic T lymphocyte-associated antigen 4

DILI

Drug-induced liver injury

DMSO

Dimethyl sulfoxide

FACS

Fluorescence-activated cell sorting

FBS

Fetal bovine serum

FLUX

Flucloxacillin

GWAS

Genome-wide association study

HLA

Human leukocyte antigen

HSR

Hypersensitivity reaction

IDT

Idiosyncratic drug toxicity

LLNA

Local lymph node assay

LM

Littermate

PBMC

Peripheral blood mononuclear cells

PD-1

Programmed cell death protein 1

Notes

Acknowledgements

This work was supported by the Japan Society for the Promotion of Science (JSPS) (JSPS KAKENHI Grant Nos. 24390037, 25670068, 15K14995, 15H04661, 16K18932, and 17J03861), the Uehara Memorial Foundation, and the Leading Graduate School at Chiba University. The authors express their gratitude to Daiichi Sankyo Company, Limited (TaNeDS program) for beneficial advisement on this project; and Dr. Yagi, Dr. Sarkar, and Dr. Mita (Department of Immunology, Graduate School of Medicine, Chiba University) for their valuable technical support on this project.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interests in association with this manuscript.

Supplementary material

204_2017_2112_MOESM1_ESM.pdf (608 kb)
Supplementary material 1 (PDF 607 KB)
204_2017_2112_MOESM2_ESM.docx (22 kb)
Supplementary material 2 (DOCX 21 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Takeshi Susukida
    • 1
  • Shigeki Aoki
    • 1
  • Kotaro Kogo
    • 1
  • Sota Fujimori
    • 1
  • Binbin Song
    • 1
  • Cong Liu
    • 1
  • Shuichi Sekine
    • 1
  • Kousei Ito
    • 1
  1. 1.Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical SciencesChiba UniversityChibaJapan

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