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

Details

Serval ID
serval:BIB_B1B08720EB6C
Type
Article: article from journal or magazin.
Collection
Publications
Title
Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response.
Journal
Clinical and Experimental Allergy
Author(s)
Yun J., Mattsson J., Schnyder K., Fontana S., Largiadèr C.R., Pichler W.J., Yerly D.
ISSN
1365-2222 (Electronic)
ISSN-L
0954-7894
Publication state
Published
Issued date
2013
Peer-reviewed
Oui
Volume
43
Number
11
Pages
1246-1255
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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 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
Adult, Aged, Aged, 80 and over, Aldehyde Oxidase/genetics, Aldehyde Oxidase/metabolism, Alleles, Allopurinol/administration & dosage, Allopurinol/adverse effects, Cross Reactions/immunology, Dose-Response Relationship, Drug, Drug Hypersensitivity/genetics, Drug Hypersensitivity/immunology, Gout Suppressants/administration & dosage, Gout Suppressants/adverse effects, 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
Pubmed
Web of science
Create date
09/11/2014 18:27
Last modification date
20/08/2019 16:20
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