Activation of T cells by carbamazepine and carbamazepine metabolites.

Abstract

BACKGROUND:

T-cell-mediated hypersensitivity is a rare but serious manifestation of drug therapy.

OBJECTIVES:

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.

CONCLUSION:

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.

CLINICAL IMPLICATIONS:

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: Ying Wu, Joseph P Sanderson, John Farrell, Nicola S Drummond, Anita Hanson, Elizabeth Bowkett, Neil Berry, Andrew V Stachulski, Stephen E Clarke, Werner J Pichler, Munir Pirmohamed, B Kevin Park, Dean J Naisbitt
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 118 Issue 1 Pg. 233-41 (Jul 2006) ISSN: 0091-6749 [Print] United States
• PMID: 16815161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dibenzazepines
• Carbamazepine
• dibenzazepine
• Oxcarbazepine

Topics

• Adult
• Aged
• Antigen Presentation
• Carbamazepine (analogs & derivatives, pharmacology)
• Cross Reactions
• Dibenzazepines (pharmacology)
• Female
• Humans
• Lymphocyte Activation (drug effects)
• Male
• Middle Aged
• Oxcarbazepine
• T-Lymphocytes (immunology)