title: Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response.
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 (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
  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.
authors.affiliation: Department of Rheumatology, Clinical Immunology and Allergology, Inselspital/University Hospital of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Yun
authors.forename: J
authors.initials: J
authors.lastname: Mattsson
authors.forename: K
authors.initials: K
authors.lastname: Schnyder
authors.forename: S
authors.initials: S
authors.lastname: Fontana
authors.forename: C R
authors.initials: CR
authors.lastname: Largiadèr
authors.forename: W J
authors.initials: WJ
authors.lastname: Pichler
authors.forename: D
authors.initials: D
authors.lastname: Yerly
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042931:Aldehyde Oxidase / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000493:Allopurinol / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism; D003429:Cross Reactions / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000235:genetics / Q000276:immunology*; D006074:Gout Suppressants / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008875:Middle Aged; D010117:Oxypurinol / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014968:Xanthine Dehydrogenase / Q000235:genetics / Q000378:metabolism
chemical_list: D006074:Gout Suppressants; D015235:HLA-B Antigens; D000493:Allopurinol; D014968:Xanthine Dehydrogenase; C526436:AOX1 protein, human; D042931:Aldehyde Oxidase; D010117:Oxypurinol
keywords: HLA; HLA-B*58:01; T cells; allopurinol; avidity; dose; drug hypersensitivity; oxypurinol; severe cutaneous adverse reaction