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␤ 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 Ϯ 24.2 [10 g ml Ϫ1 ]) but not control patients (stimulation index: 1.2 Ϯ 0.4 [10 g ml Ϫ1 ]) proliferated upon stimulation with CBZ. Of 44 CBZ-specific T cell clones generated, 10 were selected for further analysis. All 10 clones were either CD4ϩ or CD4ϩ/ CD8ϩ, 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.

Mechanisms of drug-induced liver injury

“…Evidence to support these hypotheses is gained by the detection of drug-specifi c antibodies and T cells in some patients with DILI. [15][16][17][18][19][20][21] This review will focus on the involvement of the innate and adaptive immune systems in the pathogenesis of DILI.…”

Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage

“…In this alternate hypothesis, there is a direct, non-convalent binding of the drug to the T cell receptor to specific T cell clones. Drug-specific T cells have been identified for lamotrigine and carbamazepine (25,26). Handoko and coworkers have also confirmed that the association for T cellmediated reactions was strongest in cutaneous reactions (13).…”

Pathogenesis and Clinical Approaches to Anticonvulsant Hypersensitivity Syndrome: Current State of Knowledge

“…Naisbitt et al observed in patients with CBZinduced AHS a clonal proliferation of CD4+ or CD4+/CD8+ cells, associated to the interferon-y secretion and to cytotoxic effects (27).…”

“…The variability in the clinical presentation ofAHS, such as epidermal eruptions and mucosal blistering in SJS, epidermal necrosis and delamination in TEN, or eosinophilia in DRESS, is likely to reflect host-specific metabolic and immunologic reactions associated with T-cell-mediated responses in these tissues (27)(28)(30)(31). These reactions include varying levels of cytochrome induction: MHC/non-MHC-dependent T-cell activation; involvement of cytotoxic CD8+ and CD4+ mediated responses; expression of adhesion and homing molecules on keratinocytes; chemokine release with infiltration by monocytes/macrophages and eosinophils.…”