*Purpose: Hepatic ischemia/reperfusion injury (IRI) is the leading cause of early graft dysfunction and contributes to the shortage of donor organs. 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 their time in the systemic circulation, therefore improving their efficacy. Here, we PEGylate IDO and test the efficacy of this targeted IDO delivery strategy to control the local hepatic inflammatory response in a mouse model of warm liver IRI.

*Methods: To achieve this, we used a well-establishedmouse model of partial hepatic ischemia reperfusion injury. 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 were intravenously administered 48 hours prior to inducing ischemic injury.

*Results: IDO PEGylation significantly improved hepatic Ischemia reperfusion injury; plasma levels of aspartate alanine aminotransferase at 6 hours after reperfusion were significantly lower in the PEG-IDO group, when compared with those in PBS group (P=0.008). Histological analysis showed significantly less congestion, necrosis, and vacuolization in the PEG-IDO group compared with those in PBS groups (P<0.001) as assessed by Suzuki score. Furthermore, while control mice demonstrated a marked increase in the infiltration of activated inflammatory leukocytes, these were significantly reduced in the livers of mice administered PEGylated-IDO.

*Conclusions: The results in this study indicate that PEG-IDO preconditioning protects livers from the uncontrolled development of warm hepatic IRI. We suggest that this immune-modulatory approach may be clinically useful as a protective measure against liver IRI.

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