*Purpose: Hepatic ischemia/reperfusion injury (IRI) is the leading cause of early graft dysfunction and contributes to the shortage of donor liver grafts. However, despite its obvious clinical importance, there are no effective therapies to prevent or treat this condition. Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that catalyzes the catabolism of the essential amino acid tryptophan to the product kynurenine. It is well known for inducing a powerful immunosuppressive metabolic programming. To date, studies have mostly focused on prolonging graft survival by overexpressing IDO in the transplanted tissue. PEGylation of therapeutic proteins reduces their immunogenicity and extends systemic circulation time. Here, we PEGylate IDO and evaluate efficacy and safety of this IDO delivery strategy to control the local hepatic inflammatory response in a mouse model of warm hepatic IRI

*Methods: We used a well-established mouse model of partial hepatic IRI. Partial hepatic ischemia was produced in the left and median lobes for 90 minutes followed by 6 hours reperfusion. Male 8-12 week old Balb/c mice were separated into 3 cohorts; PEGylated-IDO (PEG-IDO), IDO, and phosphate buffered saline (PBS) intravenously administered 48 hours prior to inducing ischemic injury.

*Results: PEGylated-IDO significantly improved hepatic IRI; plasma levels of aspartate alanine aminotransferase and alanine aminotransferase at 6 hours after reperfusion were significantly lower in the PEG-IDO group, when compared with those in PBS group (P<0.05). Histological analysis showed significantly less congestion, necrosis, and vacuolization in the PEG-IDO group compared with those in PBS groups (P<0.05) as assessed by Suzuki score. It decreased the local infiltration of the inflammatory cells such as T cells, neutrophils, and macrophages, and it reduced the expression of proinflammatory cytokines and chemokines. Furthermore, apoptosis, as measured by the number of TUNEL+ hepatocytes, was also suppressed in PEG-IDO treated mice.

*Conclusions: The results in this study indicate that PEG-IDO preconditioning protects livers from local inflammation and liver damage induced by hepatic IRI. This metabolic immune-modulatory approach may be a new therapeutic strategy against innate immunity-dominated liver tissue damage.

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