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

Yun, James; Mattsson, Johan; Schnyder, Karin; Fontana, Stefano; Largiadèr, Carlo R.; Pichler, Werner J.; Yerly, Daniel

doi:10.1111/cea.12184

Cited by 111 publications

(118 citation statements)

References 37 publications

(65 reference statements)

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“…A previous study reported that the starting dose was a risk factor for allopurinol hypersensitivity syndrome. 31 In addition, Yun et al 32 reported that a high concentration of allopurinol is an important factor for the generation of drug-specific T cells in the presence of the HLA-B*58:01 allele. Based on our previous retrospective cohort study, the current study showed that potentially 5.4 new cases of SCAR among 30 HLA-B*58:01-positive patients were successfully prevented with the introduction of the tolerance induction protocol.…”

Section: Discussionmentioning

confidence: 99%

An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing

Jung

Park

et al. 2015

Genetics in Medicine

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Purpose: This study was conducted to evaluate the usefulness of human leukocyte antigen (HLA) typing in preventing allopurinolinduced severe cutaneous adverse reactions (SCARs) through the application of an allopurinol tolerance induction protocol or prescription of other alternative medications in high-risk patients.Methods: HLA typing was performed in patients with chronic renal insufficiency who needed allopurinol. HLA-B*58:01-negative patients were prescribed the usual dose of allopurinol. For HLA-B*58:01-positive patients, administration of either allopurinol based on a 28-day tolerance induction protocol or alternative medications was initiated. Hypersensitivity reactions were surveyed for 90 days and compared with the result of a previous retrospective cohort study.

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Section: Discussionmentioning

confidence: 99%

An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing

Jung

Park

et al. 2015

Genetics in Medicine

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“…ALP/OXP T cell lines (TCLs) were generated by incubating lymphocytes (4-6 3 10 6 cells/2 ml in 24-well plates) with 100 mg/ml ALP or OXP (Sigma-Aldrich, Buchs, Switzerland) because this dose was shown to be effective in stimulating ALP/OXP-specific T cell responses from drug-naive donors (18). For control experiments, peptide-specific TCLs and T cell clones (TCCs) were generated using an HLA-B*58:01-restricted peptide, IaW9 (IALYLQQNW) (21).…”

Section: T Cell Line and T Cell Clone Generationmentioning

confidence: 99%

“…ALP/OXPTCCs were generated by limiting dilution, as described elsewhere (22). The specificity of TCCs was assessed by increased CD107a expression on FACS, IFN-g ELISPOT assay, or [ 51 Cr]-release assay, as previously described (15,18,23).…”

Section: T Cell Line and T Cell Clone Generationmentioning

confidence: 99%

“…First, selfpresentation of the drugs by T cells was minimized by reducing the stimulating drug concentrations. This was possible because ALP/OXP-TCLs are highly dose dependent (18). Then, ALP/OXP-specific responses could be restored by adding an excess of APCs, such as EBV-BLCLs, with higher MHC density in the presence of the drug.…”

Section: Hla-restriction Analysismentioning

confidence: 99%

“…We (18) showed recently that the HLA-B*58:01 allele is an important factor in generating ALP-or OXP-specific T cell responses from healthy drug-naive donors and that these responses are highly dose dependent. Furthermore, these drug-specific T cells universally lack cross-reactivity and have the ability to discriminate between structurally related ALP and OXP (Fig.…”

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confidence: 99%

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Oxypurinol Directly and Immediately Activates the Drug-Specific T Cells via the Preferential Use of HLA-B*58:01

Yun

Marcaida

Eriksson

et al. 2014

The Journal of Immunology

140

174

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Allopurinol (ALP) hypersensitivity is a major cause of severe cutaneous adverse reactions and is strongly associated with the HLA-B*58:01 allele. However, it can occur in the absence of this allele with identical clinical manifestations. The immune mechanism of ALP-induced severe cutaneous adverse reactions is poorly understood, and the T cell–reactivity pattern in patients with or without the HLA-B*58:01 allele is not known. To understand the interactions among the drug, HLA, and TCR, we generated T cell lines that react to ALP or its metabolite oxypurinol (OXP) from HLA-B*58:01+ and HLA-B*58:01− donors and assessed their reactivity. ALP/OXP-specific T cells reacted immediately to the addition of the drugs and bypassed intracellular Ag processing, which is consistent with the “pharmacological interaction with immune receptors” (p-i) concept. This direct activation occurred regardless of HLA-B*58:01 status. Although most OXP-specific T cells from HLA-B*58:01+ donors were restricted by the HLA-B*58:01 molecule for drug recognition, ALP-specific T cells also were restricted to other MHC class I molecules. This can be explained by in silico docking data that suggest that OXP binds to the peptide-binding groove of HLA-B*58:01 with higher affinity. The ensuing T cell responses elicited by ALP or OXP were not limited to particular TCR Vβ repertoires. We conclude that the drug-specific T cells are activated by OXP bound to HLA-B*58:01 through the p-i mechanism.

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Genetic Variants Associated With Phenytoin-Related Severe Cutaneous Adverse Reactions

Chung

Chang²,

Lee

et al. 2014

JAMA

261

165

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

Cited by 111 publications

References 37 publications

An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing

An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing

Oxypurinol Directly and Immediately Activates the Drug-Specific T Cells via the Preferential Use of HLA-B*58:01

Genetic Variants Associated With Phenytoin-Related Severe Cutaneous Adverse Reactions

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