Drug-specific CD4(+) T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome
- Authors
- Ye, Y. -M.; Hur, G. -Y.; Kim, S. -H.; Ban, G. -Y.; Jee, Y. -K.; Naisbitt, D. J.; Park, H. -S.; Kim, S. -H.
- Issue Date
- 2월-2017
- Publisher
- WILEY
- Citation
- BRITISH JOURNAL OF DERMATOLOGY, v.176, no.2, pp.378 - 386
- Indexed
- SCIE
SCOPUS
- Journal Title
- BRITISH JOURNAL OF DERMATOLOGY
- Volume
- 176
- Number
- 2
- Start Page
- 378
- End Page
- 386
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/84793
- DOI
- 10.1111/bjd.14839
- ISSN
- 0007-0963
- Abstract
- Background A multidrug regimen including isoniazid, rifampicin, pyrazinamide and ethambutol is commonly used as first-line treatment for tuberculosis. However, this regimen can occasionally result in severe adverse drug reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and drug-induced liver injury. The culprit drug and mechanistic basis for the hypersensitive reaction are unknown. Objectives To investigate drug-specific T-cell responses in patients with anti-tuberculosis drug (ATD)-induced cutaneous hypersensitivity and its underlying mechanism. Methods We enrolled eight patients with ATD-induced maculopapular exanthema and DRESS and performed a lymphocyte transformation test. Subsequently, drug-specific T-cell clones were generated from four of the patients who showed proliferation in response to ATDs. We measured the drug-specific proliferative responses and counted the drug-specific interferon (IFN)-gamma/granzyme B-producing cells after drug stimulation. Antihuman leukocyte antigen (HLA) class I and class II blocking antibodies were used to analyse human leukocyte antigenrestricted T-cell responses. Results Positive proliferative responses to ATDs were mostly found in patients with cutaneous hypersensitivity. Furthermore, we isolated isoniazid/rifampicin-specific T cells from patients, which consisted primarily of CD4+ T cells. Drug-specific CD4+ T cells proliferated and secreted IFN-gamma/granzyme B when stimulated with isoniazid or rifampicin, respectively. Isoniazid-responsive T-cell clones did not proliferate in the presence of rifampicin and vice versa. Drug-specific T-cell responses were blocked in the presence of anti-HLA class II antibodies. Conclusions This study identifies the presence of isoniazid/rifampicin-specific T cells in patients with ATD-induced maculopapular exanthema and DRESS. Furthermore, it highlights the important role of drug-specific T-cell immune responses in the pathogenesis of these reactions.
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