Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response
Article first published online: 24 OCT 2013
© 2013 John Wiley & Sons Ltd
Clinical & Experimental Allergy
Volume 43, Issue 11, pages 1246–1255, November 2013
How to Cite
Clinical & Experimental Allergy, 2013 (43) 1246–1255., , , , , and ,
- Issue published online: 24 OCT 2013
- Article first published online: 24 OCT 2013
- Accepted manuscript online: 14 AUG 2013 01:55AM EST
- Manuscript Accepted: 24 JUL 2013
- Manuscript Revised: 11 JUL 2013
- Manuscript Received: 4 JUN 2013
- Swiss Center for Applied Human Toxicology
- Swiss National Science Foundation. Grant Number: 310030-129828-1
- drug hypersensitivity;
- severe cutaneous adverse reaction;
- T cells
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.
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.
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.
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.