Evaluation of immune-mediated idiosyncratic drug toxicity using chimeric HLA transgenic mice
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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.
KeywordsIdiosyncratic drug toxicity Immunotoxicology Human leucocyte antigen In vivo model Abacavir
Bovine serum albumin
Cytotoxic T lymphocyte-associated antigen 4
Drug-induced liver injury
Fluorescence-activated cell sorting
Fetal bovine serum
Genome-wide association study
Human leukocyte antigen
Idiosyncratic drug toxicity
Local lymph node assay
Peripheral blood mononuclear cells
Programmed cell death protein 1
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.
- Khare SD, Hansen J, Luthra HS, David CS (1996) HLA-B27 heavy chains contribute to spontaneous inflammatory disease in B27/human beta2-microglobulin (beta2m) double transgenic mice with disrupted mouse beta2m. J Clin Invest 98(12):2746–2755. https://doi.org/10.1172/JCI119100 CrossRefPubMedPubMedCentralGoogle Scholar
- Marron MP, Graser RT, Chapman HD, Serreze DV (2002) Functional evidence for the mediation of diabetogenic T cell responses by HLA-A2.1 MHC class I molecules through transgenic expression in NOD mice. Proc Natl Acad Sci U S A 99(21):13753–13758. https://doi.org/10.1073/pnas.212221199 CrossRefPubMedPubMedCentralGoogle Scholar
- WHO (2016) Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. Who guidelines approved by the guidelines review committee, 2nd edn, WHO, GenevaGoogle Scholar