title: Drug-specific CD4+T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome.
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.
  
  
  OBJECTIVE
  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)-γ/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-γ/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.
authors.affiliation: Department of Allergy & Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Y-M
authors.initials: YM
authors.lastname: Ye
authors.affiliation: Department of Internal Medicine, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: G-Y
authors.initials: GY
authors.lastname: Hur
authors.affiliation: Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Allergy & Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: G-Y
authors.initials: GY
authors.lastname: Ban
authors.affiliation: Department of Internal Medicine, Dankook University College of Medicine, Cheonan, South Korea.
authors.forename: Y-K
authors.initials: YK
authors.lastname: Jee
authors.affiliation: MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, The University of Liverpool, Liverpool, U.K.
authors.forename: D J
authors.initials: DJ
authors.lastname: Naisbitt
authors.affiliation: Department of Allergy & Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: H-S
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Allergy & Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea.|Translational Research Laboratory for Inflammatory Disease, Clinical Trial Center, Ajou University Medical Center, Suwon, South Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D063926:Drug Hypersensitivity Syndrome / Q000276:immunology*; D005076:Exanthema / Q000139:chemically induced* / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007538:Isoniazid / Q000009:adverse effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000009:adverse effects / Q000276:immunology
chemical_list: D000995:Antitubercular Agents; D006680:HLA Antigens; D007538:Isoniazid; D012293:Rifampin