EXPERIMENTAL LARGE-ANIMAL MODEL OF OBLITERATIVE BRONCHIOLITIS AFTER LUNG TRANSPLANTATION

Obliterative bronchiolitis is a major cause of long-term morbidity after lung transplantation. It is characterized by small-airway inflammation and occlusion by fibrous tissue. The pathogenesis is uncertain. To study this disease, we developed a model of posttransplantation obliterative bronchiolitis using genetically defined miniature swine. Group 1 (n = 2) received a left lung autograft; group 2 (n = 7), a left lung allograft, Group 2 recipients were given cyclosporine, prednisone, and azathioprine for 3 months, then immunosuppression was tapered and discontinued over 1 month. The animals were observed for an additional 2 months, then sacrificed. Lung grafts in both groups were monitored with serial bronchoalveolar lavages and transbronchial biopsies for 6 months. After sacrifice, lung grafts underwent histopathologic and immunohistochemical examination. No allograft had histologic evidence of acute rejection or peribronchiolar infiltrate during the first 3 months of immunosuppression. During the tapering period, airway changes characterized by severe peribronchiolar lymphocytic infiltrates were seen. Bronchoalveolar lavages of allografts showed significantly increased lymphocyte counts with CD8+ cells predominating. After the discontinuation of immunosuppression, transbronchial biopsy and autopsy specimens showed progressive fibrous inflammatory occlusion of bronchioles. Immunohistochemical staining demonstrated increased expression of MCH class II antigen on the bronchiolar epithelium and increased dendritic cells and CD4+ lymphocytes. None of these changes were seen in group 1. Our findings suggest obliterative bronchiolitis is an immunologically mediated phenomenon related to chronic graft rejection after lung transplantation. This model will allow systematic study of the pathogenesis of obliterative bronchiolitis and possible therapeutic intervention.