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

J Allergy Clin Immunol. 2007 Apr;119(4):973-81. doi: 10.1016/j.jaci.2006.12.617. Epub 2007 Feb 22.

Abstract

Background: Hypersensitivity 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.

Objectives: The aim of these studies was to generate and characterize CD4(+), CD8(+), and CD4(+)CD8(+) T cells in patients with carbamazepine hypersensitivity.

Methods: Carbamazepine-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.

Results: Ninety 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-gamma and IL-5. A panel of CD11a(+)CD27(-) clones differentially expressed the receptors CXCR4, CCR4, CCR5, CCR8, CCR9, and CCR10.

Conclusion: Carbamazepine-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 implications: Carbamazepine-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigen Presentation
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Carbamazepine / immunology*
  • Carbamazepine / pharmacology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Clone Cells
  • Cytotoxicity, Immunologic / drug effects
  • Drug Hypersensitivity / immunology*
  • Drug Hypersensitivity / pathology
  • Epitopes, T-Lymphocyte / immunology*
  • Epitopes, T-Lymphocyte / metabolism
  • Female
  • Humans
  • Immunophenotyping
  • Lymphocyte Activation / drug effects
  • Male

Substances

  • Epitopes, T-Lymphocyte
  • Carbamazepine