title: Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones.
abstract: 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 beta phenotype. Proliferation, cytotoxicity, and cytokine secretion were measured by [(3)H]thymidine incorporation, (51)Cr 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 microg ml(-1)]) but not control patients (stimulation index: 1.2 +/- 0.4 [10 microg 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 alpha beta T cell receptor, secreted IFN-gamma, 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.
authors.affiliation: Department of Pharmacology, The University of Liverpool, Liverpool, United Kingdom. dnes@liv.ac.uk
authors.forename: D J
authors.initials: DJ
authors.lastname: Naisbitt
authors.forename: M
authors.initials: M
authors.lastname: Britschgi
authors.forename: G
authors.initials: G
authors.lastname: Wong
authors.forename: J
authors.initials: J
authors.lastname: Farrell
authors.forename: J P H
authors.initials: JP
authors.lastname: Depta
authors.forename: D W
authors.initials: DW
authors.lastname: Chadwick
authors.forename: W J
authors.initials: WJ
authors.lastname: Pichler
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D002220:Carbamazepine / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D003429:Cross Reactions; D016207:Cytokines / Q000378:metabolism*; D004342:Drug Hypersensitivity / Q000473:pathology*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; D002220:Carbamazepine