Generation and characterization of antigen-specific CD4+, CD8+, and CD4+CD8+ T-cell clones from patients with carbamazepine hypersensitivity

BackgroundHypersensitivity is a serious manifestation of anticonvulsant therapy characterized by infiltration of the epidermis and dermis by activated CD8+ and CD4+ T-cells, respectively. Attempts to characterize drug-specific CD8+ T cells have been largely unsuccessful.ObjectivesThe aim of these studies was to generate and characterize CD4+, CD8+, and CD4+CD8+ T cells in patients with carbamazepine hypersensitivity.MethodsCarbamazepine-specific T-cell clones were generated from 5 patients by using modified cloning methodologies. Cell surface receptor phenotype, functionality, and mechanisms of antigen presentation were then compared.ResultsNinety CD4+, 23 CD8+, and 14 CD4+CD8+ carbamazepine-specific T-cell clones were generated. CD4+ T-cell clones proliferated vigorously with carbamazepine associated with MHC class II but exhibited little cytotoxic activity. In contrast, most CD8+ T cells proliferated weakly but effectively killed target cells via an MHC class I or MHC class II restricted, perforin-dependent pathway. CD4+CD8+ T cells displayed characteristics similar to those of CD4+ T cells; however, drug stimulation was demonstrable in the absence of antigen-presenting cells. Carbamazepine was presented to CD4+, CD8+, and CD4+CD8+ T cells in the absence of antigen processing. Drug stimulation resulted in the secretion of IFN-γ and IL-5. A panel of CD11a+CD27− clones differentially expressed the receptors CXCR4, CCR4, CCR5, CCR8, CCR9, and CCR10.ConclusionCarbamazepine-specific CD4+, CD8+, and CD4+CD8+ T cells exist in the peripheral circulation of hypersensitive patients, often many years after the resolution of clinical manifestations.Clinical implicationsCarbamazepine-specific CD4+, CD8+, and CD4+CD8+ T cells displaying different effector functions and homing characteristics persist in hypersensitive patients' blood for many years after resolution of clinical symptoms.