Vol. 63, Issue 3, 732-741, March 2003

Hypersensitivity Reactions to Carbamazepine: Characterization of the Specificity, Phenotype, and Cytokine Profile of Drug-Specific T Cell Clones

D. J. Naisbitt, M. Britschgi, G. Wong, J. Farrell, J. P. H. Depta, D. W. Chadwick, W. J. Pichler, M. Pirmohamed, and B. K. Park

Departments of Pharmacology and Therapeutics (D.J.N., J.F., M.P., B.K.P.), Dermatology (G.W.), and Neurological Sciences (D.W.C.), The University of Liverpool, Liverpool, United Kingdom; and Clinic for Rheumatology & Clinical Immunology/Allergology, Inselspital, University of Bern, Bern, Switzerland (M.B., J.P.H.D., W.J.P.)

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 V 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 ml¹]) but not control patients (stimulation index: 1.2 ± 0.4 [10 µg ml¹]) 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 T cell receptor, secreted IFN-, 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.