Activation of T cells by carbamazepine and carbamazepine metabolites.
BACKGROUND
T-cell-mediated hypersensitivity is a rare but serious manifestation of drug therapy.


OBJECTIVE
To explore the mechanisms of drug presentation to T cells and the possibility that generation of metabolite-specific T cells may provoke cross-sensitization between drugs.


METHODS
A lymphocyte transformation test was performed on 13 hypersensitive patients with carbamazepine, oxcarbazepine, and carbamazepine metabolites. Serial dilution experiments were performed to generate drug (metabolite)-specific T-cell clones to explore the structural basis of the T-cell response and mechanisms of antigen presentation. 3-Dimensional energy-minimized structures were generated by using computer modeling. The role of drug metabolism was analyzed with 1-aminobenzotriazole.


RESULTS
Lymphocytes and T-cell clones proliferated with carbamazepine, oxcarbazepine, and some (carbamazepine 10,11 epoxide, 10-hydroxy carbamazepine) but not all stable carbamazepine metabolites. Structure activity studies using 29 carbamazepine (metabolite)-specific T-cell clones revealed 4 patterns of drug recognition, which could be explained by generation of preferred 3-dimensional structural conformations. T cells were stimulated by carbamazepine (metabolites) bound directly to MHC in the absence of processing. The activation threshold for T-cell proliferation varied between 5 minutes and 4 hours. 1-Aminobenzotriazole, which inhibits cytochrome P450 activity, did not prevent carbamazepine-related T-cell proliferation. Substitution of the terminal amine residue of carbamazepine with a methyl group diminished T-cell proliferation.


CONCLUSIONS
These data show that carbamazepine and certain stable carbamazepine metabolites stimulate T cells rapidly via a direct interaction with MHC and specific T-cell receptors.


CONCLUSIONS
Some patients with a history of carbamazepine hypersensitivity possess T cells that cross-react with oxcarbazepine, providing a rationale for cross-sensitivity between the 2 drugs.
Wu
Ying
Y
Department of Pharmacology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
Sanderson
Joseph P
JP
Farrell
John
J
Drummond
Nicola S
NS
Hanson
Anita
A
Bowkett
Elizabeth
E
Berry
Neil
N
Stachulski
Andrew V
AV
Clarke
Stephen E
SE
Pichler
Werner J
WJ
Pirmohamed
Munir
M
Park
B Kevin
BK
Naisbitt
Dean J
DJ
D000328:Adult; D000368:Aged; D017951:Antigen Presentation; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003429:Cross Reactions; D003984:Dibenzazepines / Q000494:pharmacology; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D000078330:Oxcarbazepine; D013601:T-Lymphocytes / Q000276:immunology*
D003984:Dibenzazepines; D002220:Carbamazepine; C527817:dibenzazepine; D000078330:Oxcarbazepine