Airway Epithelium is the Primary Target of Allograft Rejection in Murine Obliterative Airway Disease

Murine heterotopic tracheal allografts develop obliterative airway disease (OAD), a suitable model of chronic lung allograft rejection. This model, however, fails to account for the behavior of the allograft when adjacent to recipient airway tissues, particularly the epithelium. This study was performed to determine the immunologic role of the epithelium in development of OAD. BALB/c (H2^d) tracheal allografts were transplanted orthotopically into C57BL/6 (H2^b) mice and harvested 14-150 days post-transplantation. The phenotype of the allograft epithelium after orthotopic transplantation was determined with immunofluorescent staining. Orthotopic BALB/c tracheal allografts harvested at 28 days were re-transplanted heterotopically into BALB/c or C57BL/6 mice, harvested after 28 days, and assessed for OAD. Orthotopic allografts displayed mild cellular infiltration, no fibrosis and preserved epithelium at 28 days post-transplant. The presence of recipient-derived epithelium within the allograft was demonstrated with immunofluorescent staining at day 14. Significantly, BALB/c orthotopic allografts re-transplanted heterotopically into BALB/c mice developed OAD by day 28, whereas BALB/c orthotopic allografts re-transplanted heterotopically into C57BL/6 mice did not. Repopulation of orthotopic tracheal allografts with recipient-derived epithelium confers a protective effect against OAD after heterotopic re-transplantation. This indicates that the airway epithelium plays a crucial role in OAD development.