Details

Autor(en) / Beteiligte

• Wu, Ying, MSc
• Farrell, John, BSc
• Pirmohamed, Munir, MRCP
• Park, B. Kevin, PhD
• Naisbitt, Dean J., PhD

Titel

Generation and characterization of antigen-specific CD4+ , CD8+ , and CD4+ CD8+ T-cell clones from patients with carbamazepine hypersensitivity

Ist Teil von

• Journal of allergy and clinical immunology, 2007-04, Vol.119 (4), p.973-981

Ort / Verlag

New York, NY: Mosby, Inc

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• Background Hypersensitivity is a serious manifestation of anticonvulsant therapy characterized by infiltration of the epidermis and dermis by activated CD8+ and CD4+ T-cells, respectively. Attempts to characterize drug-specific CD8+ T cells have been largely unsuccessful. Objectives The aim of these studies was to generate and characterize CD4+ , CD8+ , and CD4+ CD8+ T cells in patients with carbamazepine hypersensitivity. Methods Carbamazepine-specific T-cell clones were generated from 5 patients by using modified cloning methodologies. Cell surface receptor phenotype, functionality, and mechanisms of antigen presentation were then compared. Results Ninety CD4+ , 23 CD8+ , and 14 CD4+ CD8+ carbamazepine-specific T-cell clones were generated. CD4+ T-cell clones proliferated vigorously with carbamazepine associated with MHC class II but exhibited little cytotoxic activity. In contrast, most CD8+ T cells proliferated weakly but effectively killed target cells via an MHC class I or MHC class II restricted, perforin-dependent pathway. CD4+ CD8+ T cells displayed characteristics similar to those of CD4+ T cells; however, drug stimulation was demonstrable in the absence of antigen-presenting cells. Carbamazepine was presented to CD4+ , CD8+ , and CD4+ CD8+ T cells in the absence of antigen processing. Drug stimulation resulted in the secretion of IFN-γ and IL-5. A panel of CD11a+ CD27− clones differentially expressed the receptors CXCR4, CCR4, CCR5, CCR8, CCR9, and CCR10. Conclusion Carbamazepine-specific CD4+ , CD8+ , and CD4+ CD8+ T cells exist in the peripheral circulation of hypersensitive patients, often many years after the resolution of clinical manifestations. Clinical implications Carbamazepine-specific CD4+ , CD8+ , and CD4+ CD8+ T cells displaying different effector functions and homing characteristics persist in hypersensitive patients' blood for many years after resolution of clinical symptoms.