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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, YM  | Hur, GY | Kim, SH | Ban, GY  | Jee, YK | Naisbitt, DJ | Park, HS  | Kim, SH
Citation
The British journal of dermatology, 176(2). : 378-386, 2017
Journal Title
The British journal of dermatology
ISSN
0007-09631365-2133
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 antituberculosis 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 antigen-restricted 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.
MeSH

DOI
10.1111/bjd.14839
PMID
27373553
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Allergy
Journal Papers > Hospital > Clinical Trial Center
Ajou Authors
김, 승현  |  박, 해심  |  반, 가영  |  예, 영민
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