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


OBJECTIVE
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.


CONCLUSIONS
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.


CONCLUSIONS
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.
Wu
Ying
Y
Department of Pharmacology, University of Liverpool, Liverpool, UK.
Farrell
John
J
Pirmohamed
Munir
M
Park
B Kevin
BK
Naisbitt
Dean J
DJ
D000328:Adult; D000368:Aged; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002220:Carbamazepine / Q000276:immunology* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004342:Drug Hypersensitivity / Q000276:immunology* / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male
D018984:Epitopes, T-Lymphocyte; D002220:Carbamazepine