Characterization of drug-specific T cells in lamotrigine hypersensitivity.
BACKGROUND
Lamotrigine is associated with hypersensitivity reactions, which are most commonly characterized by skin rash. An immune etiology has been postulated, though the nature of this is unclear.


OBJECTIVE
The aim of this study was to characterize the role of T cells in lamotrigine hypersensitivity.


METHODS
A lymphocyte transformation test was performed on 4 hypersensitive patients. Lymphocytes from 3 of 4 lamotrigine-hypersensitive patients proliferated when stimulated with lamotrigine. T-cell clones were generated from one patient to further characterize the nature of the T-cell involvement. Cells were characterized in terms of their phenotype, functionality, and mechanisms of antigen presentation and cytotoxicity.


RESULTS
Of the 44 drug-specific T-cell clones generated, most were CD4(+) with occasional CD8(+) cells. All clones expressed the alphabeta T-cell receptor; several Vbeta 5.1(+) or 9(+) T-cell clones were generated. All clones also expressed the skin-homing receptor cutaneous lymphocyte antigen. Lamotrigine-stimulated T cells were cytotoxic and secreted perforin, IFN-gamma, IL-5, and macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, RANTES, and I-309. Lamotrigine was present on HLA-DR and HLA-DQ by antigen-presenting cells in the absence of drug metabolism and processing. The T-cell receptor of certain clones could accommodate analogs of lamotrigine, but no cross-reactivity was seen with other anticonvulsants.


CONCLUSIONS
Our data provide evidence that T cells are involved in the pathogenesis of some lamotrigine-hypersensitivity reactions. The identification of drug-specific cells that express cutaneous lymphocyte antigen and type 1 cytokines after T-cell receptor activation is consistent with the clinical symptoms. Furthermore, identification of large numbers of Vbeta 5.1(+) T cells suggests that polymorphisms within T-cell receptor genes might act as determinants of susceptibility.
Naisbitt
Dean J
DJ
Department of Pharmacology and Therapeutics, Sherrington Building, Ashton Street, The University of Liverpool, PO Box 147, Liverpool L69 3GE, England.
Farrell
John
J
Wong
Gavin
G
Depta
Jan P H
JP
Dodd
Charlotte C
CC
Hopkins
Josephine E
JE
Gibney
Claire A
CA
Chadwick
David W
DW
Pichler
Werner J
WJ
Pirmohamed
Munir
M
Park
B Kevin
BK
D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D017951:Antigen Presentation; D002460:Cell Line; D002478:Cells, Cultured; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D003601:Cytotoxicity Tests, Immunologic; D004342:Drug Hypersensitivity / Q000175:diagnosis / Q000276:immunology*; D005260:Female; D006683:HLA-DQ Antigens / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D000077213:Lamotrigine; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology*; D014227:Triazines / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology
D000927:Anticonvulsants; D016207:Cytokines; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D014227:Triazines; D000077213:Lamotrigine