Activation of T cells by carbamazepine and carbamazepine metabolites

Wu, Ying; Sanderson, Joseph P; Farrell, John; Drummond, Nicola S; Hanson, Anita; Bowkett, Elizabeth; Berry, Neil; Stachulski, Andrew V; Clarke, Stephen E; Pichler, Werner J; Pirmohamed, Munir; Park, B Kevin; Naisbitt, Dean J (2006). Activation of T cells by carbamazepine and carbamazepine metabolites. Journal of allergy and clinical immunology, 118(1), pp. 233-41. St. Louis, Mo.: Mosby 10.1016/j.jaci.2006.03.005

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology

UniBE Contributor:

Pichler, Werner Joseph

ISSN:

0091-6749

ISBN:

16815161

Publisher:

Mosby

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:51

Last Modified:

17 Mar 2015 21:55

Publisher DOI:

10.1016/j.jaci.2006.03.005

PubMed ID:

16815161

Web of Science ID:

000239184800029

URI:

https://boris.unibe.ch/id/eprint/21727 (FactScience: 13393)

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