title: Mild isoniazid-induced liver injury in humans is associated with an increase in Th17 cells and T cells producing IL-10.
abstract: Isoniazid (INH) remains a mainstay for the treatment of tuberculosis despite the fact that it can cause liver failure. The mechanism of INH-induced liver injury remains controversial. It had been proposed that the mechanism involves metabolic idiosyncrasy based on the observations that liver injury is not usually associated with fever, rash, or prompt increase in alanine aminotransferase (ALT) upon rechallenge. In the present study, we found that patients who were treated with INH because of a positive tuberculosis (TB) skin test and developed a small increase in ALT had an increase in Th17 cells as well as T cells that produce interleukin (IL)-10, which suggests stimulation of an adaptive immune response. Th17 cells are considered inflammatory and could be involved in causing the liver injury. IL-10 is considered anti-inflammatory and could be the reason that more serious liver injury did not occur. These changes were not observed in patients who did not have an increase in ALT. These are the first data to show a change in the T cell profile in patients with mild INH-induced liver injury; however, it is difficult to determine whether these changes were the cause or the result of the liver injury. Nevertheless, together with other studies, the data suggest that INH-induced liver injury is immune-mediated, with mild injury resulting in immune tolerance.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
authors.forename: Imir G
authors.initials: IG
authors.lastname: Metushi
authors.forename: Xu
authors.initials: X
authors.lastname: Zhu
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gardam
authors.forename: Jack
authors.initials: J
authors.lastname: Uetrecht
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D007538:Isoniazid / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D058504:Th17 Cells / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D016753:Interleukin-10; D007538:Isoniazid