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

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 ‐ TCL s) 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 ‐ TCL s 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.