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Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2013
Author Yun James Sip, Mattsson J., Schnyder Karin, Fontana Stefano, Largíadér Carlo Rodolfo, Pichler Werner Joseph, Yerly Daniel,
Project Investigating the primary immune response against drugs in humans
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Original article (peer-reviewed)

Journal Clinical and Experimental Allergy
Volume (Issue) 43(11)
Page(s) 1246 - 1255
Title of proceedings Clinical and Experimental Allergy
DOI 10.1111/cea.12184

Abstract

Background: Allopurinol is a main cause of severe cutaneous adverse reactions (SCAR). How allopurinol induces hypersensitivity remains unknown. Pre-disposing factors are the presence of the HLA-B*58:01 allele, renal failure and possibly the dose taken. Objective: Using an in vitro model, we sought to decipher the relationship among allopurinol metabolism, HLA-B*58:01 phenotype and drug concentrations in stimulating drug-specific T cells. Methods: Lymphocyte transformation test (LTT) results of patients who had developed allopurinol hypersensitivity were analysed. We generated allopurinol or oxypurinol-specific T cell lines (ALP/OXP-TCLs) from allopurinol naïve HLA-B*58:01+ and HLA-B*58:01- individuals using various drug concentrations. Their reactivity patterns were analysed by flow cytometry and 51Cr release assay. Results: Allopurinol allergic patients are primarily sensitized to oxypurinol in a dose-dependent manner. TCL induction data show that both the presence of HLA-B*58:01 allele and high concentration of drug are important for the generation of drug-specific T cells. The predominance of oxypurinol-specific lymphocyte response in allopurinol allergic patients can be explained by the rapid conversion of allopurinol to oxypurinol in vivo rather than to its intrinsic immunogenicity. OXP-TCLs do not recognize allopurinol and vice versa. Finally, functional avidity of ALP/OXP-TCL is dependent on both the induction dose and HLA-B*58:01 status. Conclusions and Clinical Relevance: This study establishes the important synergistic role of drug concentration and HLA-B*58:01 allele in the allopurinol or oxypurinol-specific T cell responses. Despite the prevailing dogma that Type B adverse drug reactions are dose independent, allopurinol hypersensitivity is primarily driven by oxypurinol-specific T cell response in a dose-dependent manner, particular in the presence of HLA-B*58:01 allele. © 2013 John Wiley & Sons Ltd.
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