Article: article from journal or magazin.
Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01.
Journal of Immunology
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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.
Allopurinol/chemistry, Allopurinol/immunology, Binding, Competitive/immunology, CD8-Positive T-Lymphocytes/drug effects, CD8-Positive T-Lymphocytes/immunology, Calcium/immunology, Calcium/metabolism, Cells, Cultured, Flow Cytometry, HLA-B Antigens/chemistry, HLA-B Antigens/genetics, Humans, Lymphocyte Activation/drug effects, Lymphocyte Activation/genetics, Lysosomal-Associated Membrane Protein 1/immunology, Lysosomal-Associated Membrane Protein 1/metabolism, Models, Molecular, Molecular Structure, Oxypurinol/chemistry, Oxypurinol/immunology, Protein Binding/immunology, Protein Structure, Tertiary, Receptors, Antigen, T-Cell/immunology, Receptors, Antigen, T-Cell/metabolism, T-Lymphocytes/drug effects, T-Lymphocytes/immunology
Web of science
Last modification date