title: Activation of T cells by carbamazepine and carbamazepine metabolites.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Sanderson
authors.forename: John
authors.initials: J
authors.lastname: Farrell
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Drummond
authors.forename: Anita
authors.initials: A
authors.lastname: Hanson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bowkett
authors.forename: Neil
authors.initials: N
authors.lastname: Berry
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Stachulski
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Clarke
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Pichler
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Naisbitt
mesh_terms: 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*
chemical_list: D003984:Dibenzazepines; D002220:Carbamazepine; C527817:dibenzazepine; D000078330:Oxcarbazepine