Tolvaptan- and Tolvaptan-Metabolite-Responsive T Cells in Patients with Drug-Induced Liver Injury.

Andrew Gibson,Kanoot Jaruthamsophon,Dean J. Naisbitt,Sean Hammond,Sharin Roth,Merrie Mosedale

doi:10.1021/acs.chemrestox.0c00328

Abstract

Tolvaptan is an effective drug for the treatment of autosomal dominant polycystic kidney disease, but its use is associated with a significant risk of liver injury in a small number of patients. Herein we describe the presence of tolvaptan- and tolvaptan-metabolite-responsive T cell clones within the peripheral circulation of patients with liver injury. Drug treatment of the clones resulted in a proliferative response and secretion of IFN-γ, IL-13, and the cytolytic molecule granzyme B. Future work should explore pathways of tolvaptan driven T cell activation and the role of T cells in the disease pathogenesis.

Highlights

Tolvaptan is an effective drug for the treatment of autosomal dominant polycystic kidney disease, but its use is associated with a significant risk of liver injury in a small number of patients
Tolvaptan-associated liver injury was first detected in two prospective, randomized, phase 3 clinical trials investigating its use in the treatment of autosomal dominant polycystic kidney disease: Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 (NCT00428948) and the open-label follow-on trial TEMPO 4:4 (NCT01214421).[1]
Drug-responsive T cells have recently been identified in blood of patients with other forms of drug-induced liver injury,[4,5] and in the case of flucloxacillin, T cell infiltrates were identified in a liver biopsy.[6]

Summary

Americas F 33

Upon limiting dilution and cloning from PBMC bulk cultures, tolvaptan-, DM-4103-, and DM-4107responsive TCCs were detectable in (6/8) trial subjects and were predominantly of the CD4+ phenotype. The data from our study as well as the clinical pattern of liver injury in subjects with autosomal dominant polycystic kidney disease from the TEMPO clinical trials provide supportive evidence for the role of the adaptive immune system in tolvaptan-associated liver injury. Secretion of IFN-γ, IL-22, and granzyme B is a common feature of T cells from patients with other forms of drug-induced liver injury.[4,5] additional studies should explore why IL-22 secretion was not detected from the DM-4107 clones. Activation of the clones was observed at greater than 10-fold higher concentrations than patient plasma concentrations The reason for this is not known but may be that in vitro culture conditions do not accurately mimic physiological conditions.

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