A transgenic mouse model for HLA-B*57:01-linked abacavir drug tolerance and reactivity

The Journal of Clinical Investigation
Marco CardoneMichael A Norcross

Abstract

Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8+ T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced CD8+ T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of CD4+ T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive CD8+ T cells with an effector-like and skin-homing phenotype along with CD8+ infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented CD8+ T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive CD8+ T cells dependent on both HLA genetic risk and immunoregulatory...Continue Reading

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Citations

May 22, 2018·The Journal of Clinical Investigation·Elizabeth J Phillips, Simon A Mallal
Mar 4, 2020·Acta Pharmacologica Sinica·Tai RaoDong-Sheng Ou-Yang
Aug 28, 2020·Drug Metabolism Reviews·Takeshi SusukidaKousei Ito
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Aug 10, 2019·Nature Communications·Ren-You PanShuen-Iu Hung
Mar 16, 2021·Frontiers in Immunology·Yun-Shiuan Olivia HsuChun-Bing Chen
Jun 8, 2021·Frontiers in Immunology·Patricia T IllingAnthony W Purcell
May 28, 2021·Current Opinion in Allergy and Clinical Immunology·Rebecca J HertzmanElizabeth J Phillips
Jun 19, 2021·Clinical Pharmacology and Therapeutics·Pooja DeshpandeElizabeth J Phillips
Aug 3, 2021·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Shigeki Aoki
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Feb 6, 2020·The Journal of Allergy and Clinical Immunology·Marc VocansonJean-François Nicolas
Mar 21, 2020·Journal of Dermatological Science·Wan-Chun ChangBruce C Carleton

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Methods Mentioned

BETA
biopsies
flow cytometry
transgenic
biopsy
genotyping

Software Mentioned

GraphPad
GraphPad Prism
GSEA
nSolver

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