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Multicenter Study
. 2017 Dec;14(1):31-38.
doi: 10.1080/1547691X.2016.1254305.

Development of a Modified Lymphocyte Transformation Test for Diagnosing Drug-Induced Liver Injury Associated With an Adaptive Immune Response

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Free PMC article
Multicenter Study

Development of a Modified Lymphocyte Transformation Test for Diagnosing Drug-Induced Liver Injury Associated With an Adaptive Immune Response

Jessica Whritenour et al. J Immunotoxicol. .
Free PMC article

Abstract

Drug-induced liver injury (DILI) is a growing problem. Diagnostic methods to differentiate DILI caused by an adaptive immune response from liver injury of other causes or to identify the responsible drug in patients receiving multiple drugs, herbals and/or dietary supplements (polypharmacy) have not yet been established. The lymphocyte transformation test (LTT) has been proposed as a diagnostic method to determine if a subject with an apparent hypersensitivity reaction has become sensitized to a specific drug. In this test, peripheral blood mononuclear cells (PBMC) collected from a subject are incubated with drug(s) suspected of causing the reaction. Cell proliferation, measured by the incorporation of [3H]-thymidine into new DNA, is considered evidence of a drug-specific immune response. The objectives of the current studies were to: (1) develop and optimize a modified version of the LTT (mLTT) and (2) investigate the feasibility of using the mLTT for diagnosing DILI associated with an adaptive immune response and identifying the responsible drug. PBMC collected from donors with a history of drug hypersensitivity reactions to specific drugs (manifested as skin rash) were used as positive controls for assay optimization. Following optimization, samples collected from 24 subjects enrolled in the U.S. Drug-Induced Liver Injury Network (DILIN) were tested in the mLTT. Using cytokine and granzyme B production as the primary endpoints to demonstrate lymphocyte sensitization to a specific drug, most samples from the DILIN subjects failed to respond. However, robust positive mLTT responses were observed for two of four samples from three DILIN subjects with hepatitis due to isoniazid (INH). We conclude that the mLTT, as performed here on frozen and thawed PBMC, is not a reliable test for diagnosing DILI caused by all drugs, but that it may be useful for confirming the role of the adaptive immune response in DILI ascribed to INH.

Keywords: Allergic reactions; drug-induced liver injury; drugs; hepatitis; immuno-allergic; lymphocyte transformation test; lymphocytes.

Conflict of interest statement

Declaration of interest

Authors Whritenour, Ko, Zong, Wang, Tartaro, Schneider, Olson, VanVolkenburg, Serrano, and Hayashi report no conflicts of interest. Robert Fontana has received unrestricted grant funding from BMS, Janssen, and Gilead. Dr. Chalasani has consulting agreements with Lilly, Abbvie, DS Biopharma, Tobira and NuSirt, but none represent a conflict with this manuscript. Dr. Chalasani has research support from Gilead, Intercept, and Galectin but none represent a conflict with this manuscript. Dr. Bonkovsky has received support for clinical research studies unrelated to DILI from Alnylam and Clinuvel. He serves on advisory boards of Alnylam, Clinuvel, Mitsubishi-Tanabe, and Recordati.

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