Novel action of indoleamine 2,3-dioxygenase attenuating acute lung allograft injury.
BACKGROUND
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.


OBJECTIVE
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.


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.
Liu
Hanzhong
H
Department of Pediatrics, University of Florida,Gainesville, Florida, USA.
Liu
Li
L
Fletcher
Bradley S
BS
Visner
Gary A
GA
D000208:Acute Disease; D000818:Animals; D015316:Genetic Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics*; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D011183:Postoperative Complications / Q000276:immunology / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase