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.
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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
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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.
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Susukida, T., Aoki, S., Kogo, K. et al. Evaluation of immune-mediated idiosyncratic drug toxicity using chimeric HLA transgenic mice. Arch Toxicol 92, 1177–1188 (2018). https://doi.org/10.1007/s00204-017-2112-9
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DOI: https://doi.org/10.1007/s00204-017-2112-9