Cardiac allograft tolerance induced by intra-arterial infusion of recombinant adenoviral CTLA4Ig

Background. Systemic administration of soluble recombinant fusion protein o f cytotoxic T lymphocyte antigen 4 (CTLA4Ig) induces blockade of the CD28/B 7 costimulatory pathway and promotes survival of allogeneic and xenogeneic grafts. We tested the efficacy of local expression of CTLA4Ig gene in the m yocardium, induced by transduction with a recombinant adenovirus encoding t he CTLA4Ig gene, on the survival of rat cardiac allografts. Methods. The donor hearts were perfused ex vivo with recombinant adenovirus encoding CTLA4Ig cDNA (AdCTLA4Ig) via intra-aorta coronary artery before t ransplantation. The distribution and duration of CTLA4Ig transgene expressi on in the myocardium was assessed by reverse transcriptase polymerase chain reaction (RT-PCR) or in situ RT-PCR after transplantation. Results. In situ RT-PCR demonstrated abundant expression of CTLA4Ig transge ne in the endo-myocardium of AdCTLA4Ig-perfused cardiac grafts. Lewis and B rown Norway cardiac allografts transduced with AdCTLA4Ig survived indefinit ely in nonimmunosuppressed Wistar Furth recipients. However, donor-strain s kin grafts were rejected by long-term recipients of cardiac allografts, whi ch also triggered the rejection of the primary heart grafts. Conclusions. A single ex vivo intra-aortic infusion of recombinant adenovir us encoding the CTLA4Ig gene induced efficient transduction of the endo-myo cardium and promoted the permanent survival of cardiac allografts in nonimm unosuppressed hosts. Despite the beneficial effect of local immunosuppressi on on cardiac allograft survival, the strategy failed to promote a state of donor-specific peripheral tolerance.