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

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

doi:10.1172/jci99321

Cited by 48 publications

(60 citation statements)

References 70 publications

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“…CD80 on DCs is known to bind PD-L1 and prevent the inhibitory interaction with PD-1 on CD8 + T cells and to costimulate T cells by CD28. Cardone and colleagues therefore hypothesized that blocking costimulation with CTLA-4-Ig or anti-CD80 in the CD4 + T cell-depleted Tg mice would inhibit the accumulation of reactive CD8 + T cells (10). In Tg mice, CTLA-4-Ig inhibited the accumulation of reactive CD8 + PD-1 + T lymphocytes in skin at day four, suggesting that basal expression of CD80 and CD86 is required for early transient activation of abacavir-responsive CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, Cardone et al considered why, in contrast to the in vivo findings in their mouse model, drug-reactive CD8 + ical insights to the potential mechanism of abacavir tolerance in the presence of the HLA-B*57:01 risk allele (10) The authors generated HLA-B*57:01-transgenic mice (Tg mice) and were able to show that, as in humans, drug-naive mice had drug-reactive CD8 + T lymphocytes with effector potential that could rapidly respond to abacavir stimulation in vitro. Additionally, drug-reactive CD8 + T cells expanded in vitro were shown to rapidly respond to abacavir stimulation in an HLA-B*57:01-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…T cells can be activated in vitro with or without CD4 + T cells (10). The authors compared DC maturation levels in LN cells from drug-naive mice ex vivo and in culture.…”

Section: Animal Model For Abacavir Tolerancementioning

confidence: 99%

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Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration

Phillips¹,

Mallal²

2018

Journal of Clinical Investigation

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The discovery of HLA-B*57:01-associated abacavir hypersensitivity is a translational success story that eliminated adverse reactions to abacavir through pretreatment screening and defined a mechanistic model of an altered peptide repertoire. In this issue of the JCI, Cardone et al. have developed an HLA-B*57:01-transgenic mouse model and demonstrated that CD4+ T cells play a key role in mediating tolerance to the dramatically altered endogenous peptide repertoire induced by abacavir and postulate a known mechanism by which CD4+ T cells suppress DC maturation. This report potentially explains why 45% of HLA-B*57:01 carriers tolerate abacavir and provides a framework for future studies of HLA-restricted, T cell-mediated drug tolerance and hypersensitivity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration

Phillips¹,

Mallal²

2018

Journal of Clinical Investigation

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“…This allele is additionally found to be associated with multiple systemic autoimmune disorders, such as connective tissue disorder (pBY = 3.45 x 10 -10 , BMApostOR = 1.32, 95% CI = [1.23, 1.42]), sarcoidosis (pBY = 2.04 x 10 -33 , BMApostOR = 1.58, 95% CI = [1.36, 1.84]), Sjogren's syndrome (pBY = 1.52 x 10 -15 , BMApostOR = 1.83, 95% CI = [1.61, 2.09]), and systemic lupus erythematosus (pBY = 9.50 x 10 -12 , BMApostOR = 1.79, 95% CI = [1.55, 2.06]), suggesting diverse and widespread involvement in various immune and bodily functions ( Supplementary Table 1). Additionally, we find that B*57:01 (notably associated with a spike in Alanine aminotransferase levels, among other adverse drug reactions, to the antiretroviral abacavir 37,38 ) to be associated with calculus of kidney and ureter.…”

Section: Bayesian Model Averagingmentioning

confidence: 70%

Pervasive additive and non-additive effects within the HLA region contribute to disease risk in the UK Biobank

Venkataraman

Olivieri²,

DeBoever

et al. 2020

Preprint

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The human leukocyte antigen (HLA) region is one of the most disease-associated regions of the human genome, yet even well-studied alleles in the HLA region have unknown impact on disease. Here, we study the effect of 156 HLA alleles on 677 binary phenotypes for 337,138 individuals in the UK Biobank. We assess HLA allele associations and subsequently use Bayesian Model Averaging for conditional analysis, a) replicating 88 known associations between HLA alleles and binary disease phenotypes such as cancer, and b) discovering 90 novel associations to phenotypes such as skin and reproductive tract cancers and to other phenotypes not previously associated with the HLA region (e.g. anemias and acne). We find several non-additive effects, suggesting a more complex landscape of disease-modifying effects throughout the region. Finally, we discover associations between homozygous HLA allele burden and several cancer and other phenotypes, suggesting that peptide presentation spectra as coded for by the HLA region are important in determining disease risk. Our results demonstrate the HLA region's complexity and richness while underscoring its clinical relevance.

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“…This leads to induction of skin-homing abacavir-specific CD8 + T-cells that induce skin inflammation. 17 The cyclopentyl and cyclopurine groups of abacavir sit in the D and E pockets of HLA-B*57:01, respectively. However, the cyclopropyl group extends into the F-pocket altering its shape and chemistry, accounting for the preferred accommodation of smaller amino acid moieties.…”

Section: Introductionmentioning

confidence: 99%

Modification of the cyclopropyl moiety of abacavir provides insight into the structure activity relationship between HLA‐B*57:01 binding and T‐cell activation

Thomson

Illing

Farrell

et al. 2019

Allergy

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Background Abacavir is associated with hypersensitivity reactions in individuals positive for the HLA‐B*57:01 allele. The drug binds within the peptide binding groove of HLA‐B*57:01 altering peptides displayed on the cell surface. Presentation of these HLA‐abacavir‐peptide complexes to T‐cells is hypothesized to trigger a CD8+ T‐cell response underpinning the hypersensitivity. Thus, the aim of this study was to explore the relationship between the structure of abacavir with HLA‐B*57:01 binding and the CD8+ T‐cell activation. Methods Seventeen abacavir analogues were synthesized and cytokine secretion from abacavir/abacavir analogue‐responsive CD8+ T‐cell clones was measured using IFN‐γ ELIspot. In silico docking studies were undertaken to assess the predicted binding poses of the abacavir analogues within the HLA‐B*57:01 peptide binding groove. In parallel, the effect of selected abacavir analogues on the repertoire of self‐peptides presented by cellular HLA‐B*57:01 was characterized using mass spectrometry. Results Abacavir and ten analogues stimulated CD8+ T‐cell IFN‐γ release. Molecular docking of analogues that retained antiviral activity demonstrated a relationship between predicted HLA‐B*57:01 binding orientations and the ability to induce a T‐cell response. Analogues that stimulated T‐cells displayed a perturbation of the natural peptides displayed by HLA‐B*57:01. The antigen‐specific CD8+ T‐cell response was dependent on the enantiomeric form of abacavir at both cyclopropyl and cyclopentyl regions. Conclusion Alteration of the chemical constitution of abacavir generates analogues that retain a degree of pharmacological activity, but have variable ability to activate T‐cells. Modelling and immunopeptidome analysis delineate how drug HLA‐B*57:01 binding and peptide display by antigen presenting cells relate to the activation of CD8+ T‐cells.

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

Cited by 48 publications

References 70 publications

Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration

Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration

Pervasive additive and non-additive effects within the HLA region contribute to disease risk in the UK Biobank

Modification of the cyclopropyl moiety of abacavir provides insight into the structure activity relationship between HLA‐B*57:01 binding and T‐cell activation

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