Characterization of drug-specific T cells in lamotrigine hypersensitivity

被引:174
作者
Naisbitt, DJ
Farrell, J
Wong, G
Depta, JPH
Dodd, CC
Hopkins, JE
Gibney, CA
Chadwick, DW
Pickler, WJ
Pirmohamed, M
Park, BK
机构
[1] Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3GE, Merseyside, England
[2] Univ Liverpool, Dept Dermatol, Liverpool L69 3GE, Merseyside, England
[3] Univ Bern, Inselspital, Clin Rheumatol & Clin Immunol Allergol, Bern, Switzerland
[4] Univ Liverpool, Dept Neurol Sci, Liverpool L69 3BX, Merseyside, England
基金
英国惠康基金;
关键词
lamotrigine; anticonvulsant hypersensitivity; T cells; antigen processing; cytokines; chemokines; T-cell receptors;
D O I
10.1067/mai.2003.1507
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: Lamotrigine is associated with hypersensitivity reactions, which are most commonly characterized by skin rash. An immune etiology has been postulated, though the nature of this is unclear. Objectives: The aim of this study was to characterize the role of T cells in lamotrigine hypersensitivity. Methods: A lymphocyte transformation test was performed on 4 hypersensitive patients. Lymphocytes from 3 of 4 lamotrigine-hypersensitive patients proliferated when stimulated with lamotrigine. T-cell clones were generated from one patient to further characterize the nature of the T-cell involvement. Cells were characterized in terms of their phenotype, functionality, and mechanisms of antigen presentation and cytotoxicity. Results: Of the 44 drug-specific T-cell clones generated, most were CD4(+) with occasional CD8(+) cells. All clones expressed the up T-cell receptor; several Vbeta 5.1(+) or 9(+) T-cell clones were generated. All clones also expressed the skin-homing receptor cutaneous lymphocyte antigen. Lamotrigine-stimulated T cells were cytotoxic and secreted perforin, IFN-gamma, IL-5, and macrophage inflammatory protein la, macrophage inflammatory protein 1beta, RANTES, and I-309. Lamotrigine was present on HLA-DR and HLA-DQ by antigen-presenting cells in the absence of drug metabolism and processing. The T-cell receptor of certain clones could accommodate analogs of lamotrigine, but no cross-reactivity was seen with other anticonvulsants. Conclusions: Our data provide evidence that T cells are involved in the pathogenesis of some lamotrigine-hypersensitivity reactions. The identification of drug-specific cells that express cutaneous lymphocyte antigen and type 1 cytokines after T-cell receptor activation is consistent with the clinical symptoms. Furthermore, identification of large numbers of Vbeta 5.1(+) T cells suggests that polymorphisms within T-cell receptor genes might act as determinants of susceptibility. (J Allergy Clin Immunol 2003;111:1393-1403.).
引用
收藏
页码:1393 / 1403
页数:11
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