CARDIAC ALLOGRAFT TOLERANCE INDUCED BY INTRAARTERIAL INFUSION OF RECOMBINANT ADENOVIRAL CTLA4Ig1

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Abstract
Background. Systemic administration of soluble recombinant fusion protein of cytotoxic T lymphocyte antigen 4 (CTLA4Ig) induces blockade of the CD28/B7 costimulatory pathway and promotes survival of allogeneic and xenogeneic grafts. We tested the efficacy of local expression of CTLA4Ig gene in the myocardium, induced by transduction with a recombinant adenovirus encoding the 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 transplantation. The distribution and duration of CTLA4Ig transgene expression 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 transgene in the endo-myocardium of AdCTLA4Ig-perfused cardiac grafts. Lewis and Brown Norway cardiac allografts transduced with AdCTLA4Ig survived indefinitely in nonimmunosuppressed Wistar Furth recipients. However, donor-strain skin grafts were rejected by long-term recipients of cardiac allografts, which also triggered the rejection of the primary heart grafts. Conclusions. A single ex vivo intra-aortic infusion of recombinant adenovirus encoding the CTLA4Ig gene induced efficient transduction of the endo-myocardium and promoted the permanent survival of cardiac allografts in nonimmunosuppressed hosts. Despite the beneficial effect of local immunosuppression on cardiac allograft survival, the strategy failed to promote a state of donor-specific peripheral tolerance.