The overall aim of these experiments is to test a new concept in the treatment of thoracic transplant recipients: organ-specific immunosuppression. Unlike all current immunosuppressive modalities, in which immunosuppression is delivered to the transplant recipient, directing treatment instead only to the transplanted donor organ would allow the recipient's immune system to remain intact; thus reducing the mortal risks of infection and malignancy post-transplant. This can be accomplished by ex vivo gene therapy of the donor organ--after the organ is removed from the donor and before implantation into the transplant recipient. 1) In the proposed experiments, the first aim is to achieve reliable and sufficient expression in the recipient of a reporter gene transfected into the donor organ 2) The second aim is to asses the in vivo effects of gene modification strategies to reduce adhesion molecule expression in the donor coronary microvasculature on the pathobiology of two early endpoint: a) ischemia-reperfusion events at 24 hours and b) cellular rejection and transplant arteriopathy at 7 days in a well- defined rabbit transplant model. 3) The third aim is to trial the developed methodology in perfused human hearts in an ex vivo system. 4) The fourth aim is to use gene modification as a tool to investigate the mechanisms by which local production of nitric oxide and MFkB activation interact to affect graft endothelial adhesion molecule expression in vivo.