*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, effective therapies to prevent or treat this condition remain elusive. Indoleamine 2,3-dioxygenase (IDO) catalyzes the catabolism of the essential amino acid tryptophan to the product kynurenine and is well known for inducing a powerful immunosuppressive metabolic programming and promoting the restoration of homeostasis. To date, studies have mostly focused on prolonging graft survival by overexpressing IDO in the transplanted tissue. In this study we focus on evaluating the efficacy of systemic IDO therapy to control the local hepatic inflammatory response of mouse IRI by administering PEGylated IDO (PEG-IDO) as a means of reducing its immunogenicity and extending its circulation time.

*Methods: Male 8-12 week old Balb/c mice were separated into 3 intravenous treatment cohorts; PEG-IDO, IDO, and phosphate buffered saline (PBS). 48 hours after administration mice were either subject to a sham operation or a well-established model of partial (70%) hepatic IRI with 90 minutes of ischemia and 6 hours of IRI

*Results: PEGylated-IDO significantly improves 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 and IDO treatment groups. Histological analysis of PEG-IDO treated livers showed significantly less congestion, necrosis, and vacuolization as assessed by Suzuki score. Systemic PEG-IDO therapy also decreased the local infiltration of the inflammatory cells such as CD3+ T cells, Ly-6G+ neutrophils, and CD68+ macrophages, and it reduced the expression of proinflammatory IL-6, TNF-α, IL-1βand IFN-γ. Furthermore, as measured by the number of TUNEL+ hepatocytes, apoptosis was also suppressed in PEG-IDO treated mice

*Conclusions: The results in this study indicate that redirecting tryptophan immunometabolism via PEG-IDO therapy protects livers from hepatic IR induced damage. This metabolic immune-modulatory strategy represents a new class of anti-inflammatory/immunosuppressive biologic drug for the treatment of liver inflammatory disorders

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