Characterization of Isoniazid-Specific T-Cell Clones in Patients with anti-Tuberculosis Drug-Related Liver and Skin Injury

Usui, Toru, Meng, Xiaoli ORCID: 0000-0002-7774-2075, Saide, Katy, Farrell, John ORCID: 0000-0002-8726-5997, Thomson, Paul ORCID: 0000-0001-5431-0459, Whitaker, Paul, Watson, John, French, Neil S ORCID: 0000-0002-9376-3482, Park, B Kevin ORCID: 0000-0001-8384-824X and Naisbitt, Dean J
(2017) Characterization of Isoniazid-Specific T-Cell Clones in Patients with anti-Tuberculosis Drug-Related Liver and Skin Injury. TOXICOLOGICAL SCIENCES, 155 (2). pp. 420-431.

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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.

Item Type: Article
Uncontrolled Keywords: drug hypersensitivity, T-lymphocytes, human, antigen
Depositing User: Symplectic Admin
Date Deposited: 30 Jan 2017 11:21
Last Modified: 19 Jan 2023 07:19
DOI: 10.1093/toxsci/kfw218
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