Modeling chronic lung allograft rejection in miniature swine.
BACKGROUND
The success of lung transplantation has been limited by the perplexing problem of chronic rejection. The development of a large-animal model for the systematic study of the mechanisms underlying chronic lung rejection has been problematic. We have developed a new preclinical model of chronic lung rejection using MHC-inbred miniature swine.


METHODS
Using standard operative techniques, four orthotopic left lung allografts were performed using MHC-matched, minor-antigen-mismatched donors. Recipient animals received a 12-day course of postoperative cyclosporine. Grafts were followed with open biopsies and high-resolution computed tomography. Cellular immune responses were monitored by mixed lymphocyte reaction, cytometric analysis of graft-infiltrating lymphocytes, and skin grafting.


RESULTS
All grafts survived > or = 5 months and developed manifestations of chronic rejection, including obliterative bronchiolitis, interstitial fibrosis, and occlusive vasculopathy. A mononuclear infiltrate was also present in all grafts by the fourth posttransplant month. High-resolution computed tomography demonstrated several cardinal radiographic findings known to correlate with chronic rejection. Cytometric analysis of graft-infiltrating lymphocytes showed a predominance of CD8+ cells. The development of alloreactivity in the host was confirmed by mixed lymphocyte reaction and skin grafting.


CONCLUSIONS
We report a reproducible, whole-lung, large-animal model of chronic lung rejection. In this immunogenetically defined construct, we have observed a full spectrum of histopathologic lesions that reproduce with fidelity those lesions observed in human lung transplant recipients suffering from chronic rejection. We anticipate that this preclinical model will facilitate further study of the pathogenesis and therapy of chronic lung rejection.
Allan
James S
JS
Division of Thoracic Surgery, and the Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. jallan@partners.org
Wain
John C
JC
Schwarze
Margaret L
ML
Houser
Stuart L
SL
Benjamin
Louis C
LC
Madsen
Joren C
JC
Sachs
David H
DH
D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D006084:Graft Rejection; D006085:Graft Survival; D008168:Lung / Q000473:pathology; D016040:Lung Transplantation / Q000276:immunology*; D013552:Swine; D013556:Swine, Miniature; D014184:Transplantation, Homologous