Recipient intramuscular gene transfer of active transforming growth factor-beta1 attenuates acute lung rejection.

ABSTRACT

BACKGROUND: Gene transfer into the donor graft has been demonstrated to be feasible in reducing ischemia-reperfusion injury and rejection in lung transplantation. This study was undertaken to determine whether intramuscular gene transfer into the recipient can also reduce subsequent lung graft rejection. METHODS: Brown Norway rats served as donors and F344 rats as recipients. Recipient animals were injected with 10(10) plaque-forming units of adenovirus encoding active transforming growth factor beta1 (group I, n = 6), beta-galactosidase as adenoviral controls (group II, n = 6), or normal saline without adenovirus (group III, n = 6) into both gluteus muscles 2 days before transplantation. Gene expression was confirmed by enzyme-linked immunosorbent assay. Graft function was assessed on postoperative day 5. RESULTS: Successful gene transfection and expression were confirmed by the presence of active transforming growth factor beta1 protein in muscle and plasma. Oxygenation was significantly improved in group I (group I vs II and III, 353.6 +/- 63.0 mm Hg vs 165.7 +/- 39.9 and 119.1 +/- 41.5 mm Hg; p = 0.02 and 0.004). The muscle transfected with the transforming growth factor beta1 showed granulation tissue with fibroblast accumulation. CONCLUSIONS: Intramuscular adenovirus-mediated gene transfer of active transforming growth factor beta1 into the recipients attenuates acute lung rejection as manifested by significantly improved oxygenation in transplanted lung allografts. This intramuscular transfection approach as a cytokine therapy is feasible in transplantation and may be useful in reducing rejection as well as reperfusion injury.