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A transgenic mouse model for HLA-B*57:01–linked abacavir drug tolerance and reactivity
Marco Cardone, … , David H. Margulies, Michael A. Norcross
Marco Cardone, … , David H. Margulies, Michael A. Norcross
Published May 21, 2018
Citation Information: J Clin Invest. 2018;128(7):2819-2832. https://doi.org/10.1172/JCI99321.
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Research Article Immunology

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

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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 host factors.

Authors

Marco Cardone, Karla Garcia, Mulualem E. Tilahun, Lisa F. Boyd, Sintayehu Gebreyohannes, Masahide Yano, Gregory Roderiquez, Adovi D. Akue, Leslie Juengst, Elliot Mattson, Suryatheja Ananthula, Kannan Natarajan, Montserrat Puig, David H. Margulies, Michael A. Norcross

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Figure 8

Costimulation with CD80 and CD86 supports activation of ABC-reactive Tg cells in vitro.

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Costimulation with CD80 and CD86 supports activation of ABC-reactive Tg ...
(A) Median fluorescence intensity of maturation markers and HLA-B*57:01 on CD11c+MHC-II+ DCs of LN cells from drug-naive Tg mice. Measurements were done ex vivo and after overnight culture in the absence or presence of ABC. Data are from 1 of 2 representative experiments. (B) IFN-γ in supernatants from day-5 LN cell cultures of drug-naive Tg mice. Cells were treated with ABC in the absence (none) or presence of CTLA-4–Ig, anti-CD80 mAb, or rat IgG2a isotype control. Data represent the mean ± SEM of ELISA results. Dots indicate values for individual mice (n = 5 per group). *P < 0.05 and **P < 0.005, by 1-way ANOVA with Tukey’s multiple comparisons correction.
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