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

Clin Exp Allergy. 2013 Nov;43(11):1246-55. doi: 10.1111/cea.12184.


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 (51) Cr 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.

Keywords: HLA; HLA-B*58:01; T cells; allopurinol; avidity; dose; drug hypersensitivity; oxypurinol; severe cutaneous adverse reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aldehyde Oxidase / genetics
  • Aldehyde Oxidase / metabolism
  • Alleles
  • Allopurinol / administration & dosage
  • Allopurinol / adverse effects*
  • Allopurinol / immunology
  • Allopurinol / metabolism
  • Cross Reactions / immunology
  • Dose-Response Relationship, Drug
  • Drug Hypersensitivity / genetics
  • Drug Hypersensitivity / immunology*
  • Gout Suppressants / administration & dosage
  • Gout Suppressants / adverse effects*
  • Gout Suppressants / immunology
  • HLA-B Antigens / genetics
  • HLA-B Antigens / immunology
  • Humans
  • Lymphocyte Activation / immunology
  • Middle Aged
  • Oxypurinol / immunology*
  • T-Lymphocytes / immunology*
  • Xanthine Dehydrogenase / genetics
  • Xanthine Dehydrogenase / metabolism


  • Gout Suppressants
  • HLA-B Antigens
  • Allopurinol
  • Xanthine Dehydrogenase
  • AOX1 protein, human
  • Aldehyde Oxidase
  • Oxypurinol