Published ahead of print on November 17, 2005, doi:10.1164/rccm.200509-1413OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200509-1413OC
Novel Action of Indoleamine 2,3-Dioxygenase Attenuating Acute Lung Allograft InjuryDepartment of Pediatrics and Department of Pharmacology and Therapeutics, University of Florida; and Medical Research Service, Department of Veteran Affairs Medical Center, Gainesville, Florida Correspondence and requests for reprints should be addressed to Gary A. Visner, D.O., Children's Hospital of Philadelphia, Division of Pulmonary Medicine, 34th and Civic Center Blvd., Woods Building, 5th Floor, Philadelphia, PA 19104. E-mail: visner{at}email.chop.edu Rationale: Lung allografts are prone to reperfusion injury and acute rejection, which, in addition to infiltrating lymphocytes, are accompanied by neutrophil infiltration and neutrophil-associated oxidative stress. Indoleamine 2,3-dioxygenase (IDO) is a unique cytosolic enzyme that possesses T-cell–suppressive and antioxidant properties. Objectives: The purpose of this study was to determine if genetic up-regulation of IDO could ameliorate acute lung allograft injury. Methods: Lung orthotopic transplants were performed using Lewis donors and Sprague-Dawley rat recipients (allografts) or the same strain (isografts). Plasmid-encoding human IDO was delivered to donor lungs in vivo using a nonviral gene-transfer vector, polyethylenimine. Transplanted lungs were evaluated at 6 d post-transplantation based on pulmonary function, histology, inflammatory responses, and their associated oxidative stress. Basic biology of the IDO-overexpressing lung cells was evaluated in vitro in response to external oxidant. Measurements and Main Results: This gene delivery method led to uniform transgene expression in lung tissue distributed in airway, alveolar epithelial, and endothelial cells. IDO overexpression in lung allografts resulted in a significant protective effect with improvement in functional properties (peak airway pressure and oxygenation) and histologic appearance. Although IDO was able to block local T-cell responses, it failed to abrogate neutrophilic infiltration and the inflammation-associated oxidative stress. IDO-enhanced lung cells were resistance to oxidant-induced necrosis and apoptosis by limiting intracellular reactive oxygen species formation. Conclusions: These results demonstrate that IDO prevents acute lung allograft injury through augmenting the local antioxidant defense system and inhibiting alloreactive T-cell responses.
Key Words: gene therapy • lung transplantation • oxidative stress • T cells This article has been cited by other articles:
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