TY - JOUR T1 - Hypersensitivity Reactions to Carbamazepine: Characterization of the Specificity, Phenotype, and Cytokine Profile of Drug-Specific T Cell Clones JF - Molecular Pharmacology JO - Mol Pharmacol SP - 732 LP - 741 DO - 10.1124/mol.63.3.732 VL - 63 IS - 3 AU - D. J. Naisbitt AU - M. Britschgi AU - G. Wong AU - J. Farrell AU - J. P. H. Depta AU - D. W. Chadwick AU - W. J. Pichler AU - M. Pirmohamed AU - B. K. Park Y1 - 2003/03/01 UR - http://molpharm.aspetjournals.org/content/63/3/732.abstract N2 - Administration of carbamazepine (CBZ) causes hypersensitivity reactions clinically characterized by skin involvement, eosinophilia, and systemic symptoms. These reactions have an immune etiology; however, the role of T cells is not well defined. The aim of this study was to characterize the specificity, phenotype, and cytokine profile of CBZ-specific T cells derived from hypersensitive individuals. Proliferation of blood lymphocytes was measured using the lymphocyte transformation test. CBZ-specific T cell clones were generated by serial dilution and characterized in terms of their cluster of differentiation and T cell receptor Vβ phenotype. Proliferation, cytotoxicity, and cytokine secretion were measured by [3H]thymidine incorporation, 51Cr release, and enzyme-linked immunosorbent assay, respectively. HLA blocking antibodies were used to study the involvement of antigen-presenting cells. The specificity of the drug T cell receptor interaction was studied using CBZ metabolites and other structurally related compounds. Lymphocytes from hypersensitive patients (stimulation index: 32.1 ± 24.2 [10 μg ml−1]) but not control patients (stimulation index: 1.2 ± 0.4 [10 μg ml−1]) proliferated upon stimulation with CBZ. Of 44 CBZ-specific T cell clones generated, 10 were selected for further analysis. All 10 clones were either CD4+ or CD4+/CD8+, expressed the αβ T cell receptor, secreted IFN-γ, and were cytotoxic. T-cell recognition of CBZ was dependent on the presence of HLA class II (DR/DQ)-matched antigen-presenting cells. The T cell receptor of certain clones could accommodate some CBZ metabolites, but no cross-reactivity was seen with other anticonvulsants or structural analogs. These studies characterize drug-specific T cells in CBZ-hypersensitive patients that are phenotypically different from T cells involved in other serious cutaneous adverse drug reactions. ER -