title: Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01.
abstract: 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.
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspital, University Hospital of Bern, Bern 3010, Switzerland;
authors.forename: James
authors.initials: J
authors.lastname: Yun
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Marcaida
authors.forename: Klara K
authors.initials: KK
authors.lastname: Eriksson
authors.forename: Heidi
authors.initials: H
authors.lastname: Jamin
authors.forename: Stefano
authors.initials: S
authors.lastname: Fontana
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Pichler
authors.forename: Daniel
authors.initials: D
authors.lastname: Yerly
mesh_terms: D000493:Allopurinol / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D001667:Binding, Competitive / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005434:Flow Cytometry; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010117:Oxypurinol / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D015235:HLA-B Antigens; C500126:HLA-B*58:01 antigen; D052118:Lysosomal-Associated Membrane Protein 1; D011948:Receptors, Antigen, T-Cell; D000493:Allopurinol; D010117:Oxypurinol; D002118:Calcium