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

Yun, J,; Mattsson, J,; Schnyder, K,; Fontana, S,; Largiadèr, C, R,; Pichler, W, J,; Yerly, D, (2013). Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response. Clinical and experimental allergy, 43(11), pp. 1246-1255. Blackwell Scientific Publications 10.1111/cea.12184

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory

UniBE Contributor:

Yun, James Jin Sup; Mattsson, Johan; Fontana, Stefano; Largiadèr, Carlo Rodolfo; Pichler, Werner Joseph and Yerly, Daniel

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0954-7894

Publisher:

Blackwell Scientific Publications

Language:

English

Submitter:

Stefan Kuchen

Date Deposited:

01 Apr 2014 15:37

Last Modified:

06 Nov 2015 09:19

Publisher DOI:

10.1111/cea.12184

PubMed ID:

24152157

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.42846

URI:

https://boris.unibe.ch/id/eprint/42846

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