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.
Highlights
Drug induced liver injury (DILI) is a growing problem that is under-recognized and underreported (Bonkovsky et al 2012; Chalasani et al 2008, 2014, 2015)
Due to the lack of availability of positive control samples for DILI associated with an adaptive response, peripheral blood mononuclear cells (PBMC) collected from 10 healthy donors that had previously experienced an allergic reaction to a specified drug(s) were used to evaluate the performance of the modified LTT (mLTT)
Samples from most positive control donors had a positive mLTT response when tested with their relevant respective drugs
Summary
Drug induced liver injury (DILI) is a growing problem that is under-recognized and underreported (Bonkovsky et al 2012; Chalasani et al 2008, 2014, 2015) Among reasons for this are the growing numbers of drugs, herbals and dietary supplements that are consumed by billions of persons worldwide and the difficulties encountered in establishing a diagnosis of DILI (Agarwal et al 2014). Among the major findings of this Network has been the realization that most idiosyncratic, non-dose related and unpredictable DILI is due to host immune responses to the causative drugs, herbals, or dietary supplements. Another has been that herbals and dietary supplements are becoming more frequent as causes (Navarro et al 2014; Seeff et al 2015)
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