Obliterative airway disease progresses in heterotopic airway allografts without persistent alloimmune stimulus

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Abstract
Up to 50% of human lung allografts develop chronic rejection manifested as obliterative bronchiolitis (OB). This complication frequently progresses despite maximal immunosuppression, suggesting that, once initiated, factors other than alloimmunity play a role in its progression. In animals, heterotopically transplanted allograft airways develop obliterative airway disease (OAD), an immunologically mediated lesion that is used as a preclinical model of OB. We sought to determine whether OAD would progress even after removal from the alloimmune environment. Tracheas from Lewis rats were transplanted subcutaneously into Brown Norway recipients to create allografts. After 7 or 14 days of alloimmune stimulus, these allografts were removed and retransplanted into an isogeneic environment for an additional 21 days. Histology was assessed at each time point, with quantitation of the airway epithelium and intraluminal fibroproliferation. Allografts exposed to 14 days of alloimmune stimulus had a significant loss of airway epithelium compared with grafts exposed to only 7 days ( <0.001). There was little fibroproliferation seen in either of these groups. After retransplantation, the grafts initially exposed to 7 days of alloimmune stimulus had few abnormalities. In contrast, the group exposed initially to 14 days of alloimmunity and retransplanted had near complete obliteration of the lumen with fibroproliferation (96.9% occlusion, =0.001) and absent airway epithelium. OAD progresses despite removal of alloimmunity if the initial period of alloimmune injury is sufficient. Airway epithelial loss correlated with progression to fibroproliferation, suggesting that the epithelium plays a significant role in the pathogenesis of OB.