Ex Vivo Expanded CD4+ T Cells from Kidney Transplant Recipients Combine Three Distinct Treg Gene Signatures

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Purpose: Acetaminophen (APAP) toxicity is among the leading causes of acute liver injury (ALI) world-wide, which can lead to acute liver failure (ALF).Nacetylcysteine (NAC) therapy is standard of care treatment for APAP-mediated ALI and reduces mortality, however has a narrow eff ective window after injury after which supportive care and subsequent liver transplantation for refractory injury remains the only therapy.Inhibition of HDAC-6 has demonstrated protection in other liver injury models like ischemia-reperfusion injury and is an attractive therapeutic target having limited off target eff ects.Here, HDAC-6 inhibition was evaluated as a therapy for acetaminophen-induced liver injury (AILI).Methods: AILI was assessed in C57BL/6 (WT) mice were given a sublethal dose of APAP (500mg/kg) following overnight fasting.WT mice were administered NAC (150 mg/kg), the HDAC6-inhibitor TubA (40 mg/kg), a combination of NAC and TubA, or vehicle either as pre-treatment at 16 hrs and 1 hr prior to APAP, or as therapy 1, 3, or 5 hrs post APAP injury.Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione were measured 24 hrs post-injury.Histopathological analysis by Modifi ed Suzuki scoring and mRNA expression by RT-qPCR were used to evaluate livers 24 hrs post-injury.Results: Pre-treatment with HDAC-6 inhibitor, TubA, provided signifi cant protection against APAP toxicity, both independently and in combination with NAC.NAC did not add to TubA benefi t.This was demonstrated by reduced AST (Fig. 1a) and ALT (Fig. 1b) serum levels and reduced histopathologic liver damaged (p<0.05).TubA pre-treated animals had prolonged survival post-toxicity (p<0.0001).TubA pre-treatment resulted in reduced mRNA expression of infl ammatory factors IFN-γ and IL-6, and oxidative response mediators NOS2, Nrf2, and Hmox1 as compared to vehicle-treated controls (p<0.05).Importantly, reduced (eff ective) hepatic glutathione levels remained unchanged after APAP toxicity with TubA pre-treatment as compared to fasting controls, while those treated with NAC or vehicle were depleted (Fig. 1c).In addition, when used as a therapy post-toxicity, TubA was at least as eff ective as NAC therapy compared to vehicle-treated animals in reducing AST (p<0.01) and ALT (p<0.05)levels.Conclusions: HDAC-6 inhibition mitigates AILI.Treatment with HDAC6-inhibitor TubA, pre-and post-toxicity had greater than or equal protection compared to standard of care NAC treatment, respectively.With further understanding of the underlying mechanisms, HDAC6 inhibition provides a promising therapeutic mechanism for treatment of AILI and potentially other forms of liver injury.

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