Header

UZH-Logo

Maintenance Infos

Patients with naproxen-induced liver injury display T-cell memory responses toward an oxidative (S)-O-Desmethyl Naproxen metabolite but not the acyl glucuronide


Thomson, Paul; Fragkas, Nik; Kafu, Laila M; Aithal, Guruprasad P; Lucena, M Isabel; Terracciano, Luigi; Meng, Xiaoli; Pirmohamed, Munir; Brees, Dominique; Kullak‐Ublick, Gerd A; Odermatt, Alex; Hammond, Thomas; Kammüller, Michael; Naisbitt, Dean J (2024). Patients with naproxen-induced liver injury display T-cell memory responses toward an oxidative (S)-O-Desmethyl Naproxen metabolite but not the acyl glucuronide. Allergy, 79(1):200-214.

Abstract

Background
Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (IBU) and naproxen (NAP) is associated with idiosyncratic drug-induced liver injury (DILI). Carboxylate bioactivation into reactive metabolites (e.g., acyl glucuronides, AG) and resulting T-cell activation is hypothesized as causal for this adverse event. However, conclusive evidence supporting this is lacking.

Methods
In this work, we identify CD4+ and CD8+ T-cell hepatic infiltration in a biopsy from an IBU DILI patient. Lymphocyte transformation test and IFN-γ ELIspot, conducted on peripheral blood mononuclear cells (PBMCs) of patients with NAP-DILI, were used to explore drug-specific T-cell activation. T-cell clones (TCC) were generated and tested for drug specificity, phenotype/function, and pathways of T-cell activation. Cells were exposed to NAP, its oxidative metabolite 6-O-desmethyl NAP (DM-NAP), its AG or synthesized NAP-AG human-serum albumin adducts (NAP-AG adduct).

Results
CD4+ and CD8+ T-cells from patients expressing a range of different Vβ receptors were stimulated to proliferate and secrete IFN-γ and IL-22 when exposed to DM-NAP, but not NAP, NAP-AG or the NAP-AG adduct. Activation of the CD4+ TCC was HLA-DQ-restricted and dependent on antigen presenting cells (APC); most TCC were activated with DM-NAP-pulsed APC, while fixation of APC blocked the T-cell response. Cross-reactivity was not observed with structurally-related drugs.

Conclusion
Our results confirm hepatic T-cell infiltrations in NSAID-induced DILI, and show a T-cell memory response toward DM-NAP indicating an immune-mediated basis for the adverse event. Whilst bioactivation at the carboxylate group is widely hypothesized to be pathogenic for NSAID associated DILI, we found no evidence of this with NAP.

Abstract

Background
Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (IBU) and naproxen (NAP) is associated with idiosyncratic drug-induced liver injury (DILI). Carboxylate bioactivation into reactive metabolites (e.g., acyl glucuronides, AG) and resulting T-cell activation is hypothesized as causal for this adverse event. However, conclusive evidence supporting this is lacking.

Methods
In this work, we identify CD4+ and CD8+ T-cell hepatic infiltration in a biopsy from an IBU DILI patient. Lymphocyte transformation test and IFN-γ ELIspot, conducted on peripheral blood mononuclear cells (PBMCs) of patients with NAP-DILI, were used to explore drug-specific T-cell activation. T-cell clones (TCC) were generated and tested for drug specificity, phenotype/function, and pathways of T-cell activation. Cells were exposed to NAP, its oxidative metabolite 6-O-desmethyl NAP (DM-NAP), its AG or synthesized NAP-AG human-serum albumin adducts (NAP-AG adduct).

Results
CD4+ and CD8+ T-cells from patients expressing a range of different Vβ receptors were stimulated to proliferate and secrete IFN-γ and IL-22 when exposed to DM-NAP, but not NAP, NAP-AG or the NAP-AG adduct. Activation of the CD4+ TCC was HLA-DQ-restricted and dependent on antigen presenting cells (APC); most TCC were activated with DM-NAP-pulsed APC, while fixation of APC blocked the T-cell response. Cross-reactivity was not observed with structurally-related drugs.

Conclusion
Our results confirm hepatic T-cell infiltrations in NSAID-induced DILI, and show a T-cell memory response toward DM-NAP indicating an immune-mediated basis for the adverse event. Whilst bioactivation at the carboxylate group is widely hypothesized to be pathogenic for NSAID associated DILI, we found no evidence of this with NAP.

Statistics

Citations

Dimensions.ai Metrics
3 citations in Web of Science®
3 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

8 downloads since deposited on 10 Oct 2023
8 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Life Sciences > Immunology
Uncontrolled Keywords:Immunology, Immunology and Allergy
Language:English
Date:1 January 2024
Deposited On:10 Oct 2023 16:05
Last Modified:29 Jun 2024 01:39
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0105-4538
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/all.15830
PubMed ID:37515456
Project Information:
  • : FunderMedical Research Council
  • : Grant ID
  • : Project Title
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)