EXPERIMENTAL LARGE-ANIMAL MODEL OF OBLITERATIVE BRONCHIOLITIS AFTER LUNG TRANSPLANTATION

Obliterative bronchiolitis is a major cause of long-term morbidity aft er lung transplantation. It is characterized by small-airway inflammat ion and occlusion by fibrous tissue. The pathogenesis is uncertain. To study this disease, we developed a model of posttransplantation oblit erative bronchiolitis using genetically defined miniature swine. Group 1 (n = 2) received a left lung autograft; group 2 (n = 7), a left lun g allograft, Group 2 recipients were given cyclosporine, prednisone, a nd azathioprine for 3 months, then immunosuppression was tapered and d iscontinued over 1 month. The animals were observed for an additional 2 months, then sacrificed. Lung grafts in both groups were monitored w ith serial bronchoalveolar lavages and transbronchial biopsies for 6 m onths. After sacrifice, lung grafts underwent histopathologic and immu nohistochemical examination. No allograft had histologic evidence of a cute rejection or peribronchiolar infiltrate during the first 3 months of immunosuppression. During the tapering period, airway changes char acterized by severe peribronchiolar lymphocytic infiltrates were seen. Bronchoalveolar lavages of allografts showed significantly increased lymphocyte counts with CD8+ cells predominating. After the discontinua tion of immunosuppression, transbronchial biopsy and autopsy specimens showed progressive fibrous inflammatory occlusion of bronchioles. Imm unohistochemical staining demonstrated increased expression of MCH cla ss II antigen on the bronchiolar epithelium and increased dendritic ce lls 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 tran splantation. This model will allow systematic study of the pathogenesi s of obliterative bronchiolitis and possible therapeutic intervention.