From the Cover: Characterization of Isoniazid-Specific T-Cell Clones in Patients with anti-Tuberculosis Drug-Related Liver and Skin Injury.
Isoniazid, rifampicin, pyrazinamide, and ethambutol are commonly used for the treatment of tuberculosis. Drug exposure is occasionally associated with liver and/or skin injury. The aim of this study was to determine whether drug-specific T-cells are detectable in patients with adverse reactions and if so characterize the nature of the T-cell response. Peripheral blood mononuclear cells (PBMC) from 6 patients with anti-tuberculosis drug-related adverse reactions (4 liver, 2 skin) were used to detect drug-responsive T-lymphocytes. Positive lymphocyte transformation test and/or ELIspot results were observed with all 6 patients. Over 3400 T-cell clones were generated from isoniazid, rifampicin, pyrazinamide, or ethambutol-treated PBMC. CD4+ clones from all 3 patients were activated to proliferate and secrete cytotoxic mediators (granzyme B, perforin, FasL) and effector (IFN-γ, Il-13) and regulatory (Il-10) cytokines with isoniazid, but not rifampicin, pyrazinamide, or ethambutol. Il-17 was not detected, while only 1 clone secreted Il-22. Isoniazid-responsive clones were not activated with other anti-tuberculosis drugs or isonicotinic acid albumin adducts. Activation of the clones with isoniazid was MHC class II-restricted and dependent on antigen-presenting cells. Most clones were activated rapidly even in the presence of the enzyme inhibitor 1-aminobenzotriazole. However, a time-dependent pathway of activation involving auto-oxidation of isoniazid was also observed. The discovery of isoniazid-specific CD4+ T-cell clones in patients with liver and skin injury suggests that the adaptive immune system is involved in the pathogenesis of both forms of iatrogenic disease.
MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England.
Toru
T
Usui
MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England.
Xiaoli
X
Meng
MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England.
Katy
K
Saide
MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England.
John
J
Farrell
MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England.
Paul
P
Thomson
Department of Respiratory Medicine, St James's Hospital, Leeds, England.
Paul
P
Whitaker
Department of Respiratory Medicine, St James's Hospital, Leeds, England.
John
J
Watson
MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England.
Neil S
NS
French
MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England.
B
B
Kevin Park
MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England; dnes@liverpool.ac.uk.
Dean J
DJ
Naisbitt
D000293:Adolescent; D000368:Aged; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D055985:Latent Tuberculosis / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D012871:Skin Diseases / Q000139:chemically induced / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy
D000995:Antitubercular Agents; D007538:Isoniazid
T-lymphocytes; antigen.; drug hypersensitivity; human