Prevention of small airway obliteration in a swine heterotopic lung allograft model

Background: In our swine model of obliterative bronchiolitis preventing obl iteration by the standard immunosuppression with cyclosporine, methylpredni solone, and azathioprine was not successful. The purpose of this study was to test the ability of a new immunosuppressive regimen to prevent alloimmun e reaction and obliteration of the allografts. This regimen includes the no vel macrolide SDZ RAD, i.e., 40-O-(2hydroxyethyl)-rapamycin. Methods: Donor lung allografts of 1 cm(3) were implanted sub-cutaneously in to 11 random-bred non-related domestic pigs receiving daily oral cyclospori ne (10 mg/kg) and methylprednisolone (20 mg). In addition, the animals rece ived either oral azathioprine (2 mg/kg) (Group 1) or oral SDZ RAD (1.5 mg/k g) (Group 2). Histologic alterations were graded from 0 to 3 based on repea tedly removed implants during a follow-up period of 3 months. Results: Total epithelial destruction and permanent luminal obliteration oc curred within 37 days in Group 1. After an initial grade of 2.3 +/- 0.3 des truction, epithelial recovery was evident in Group 2 (P < 0.01), and the br onchi stayed patent. Cartilaginous destruction was milder in Group 2 (P < 0 .05) than in Group 1, but chondrocytic proliferation was more intense (P < 0.05). Alveolar tissue and native structures of the bronchial wall were des troyed in Group 1, but preserved in Group 2 with total recovery after a mil d-grade initial necrosis. Conclusions: Unlike the standard triple therapy, SDZ RAD combined with cycl osporine and methylprednisolone preserves the pulmonary allografts and prev ents epithelial destruction and subsequent luminal obliteration. This sugge sts that this regimen might efficiently suppress obliterative bronchiolitis and improve long-term results in lung transplant recipients.