Research Group

  • Dr. Christiane Ferran, Principal Investigator


  • Beth Israel Deaconess Medical Center, Boston, USA


  • Protective Effect of A20 against Transplant-Associated Vasculopathy

Effective immunosuppressive regimens used in transplantation have drastically reduced the failure of vascularized grafts due to acute rejection (<10%). Chronic rejection is the major obstacle to long-term transplant function. Chronic rejection is characterized by the development of an accelerated arteriosclerosis, termed “transplant-associated vasculopathy” (TAV). TAV is particularly dramatic in cardiac transplant recipients and has become the principle cause of late death and graft dysfunction. The precise mechanisms of chronic rejection and TAV are poorly understood and likely multifactorial, with both immunological and non-immunological causes.

Numerous approaches to treating TAV (including increased immunosuppression, anti-hypertensive and lipid lowering agents) have been largely unsuccessful and carry additional toxicity. We propose a novel anti-TAV approach aimed at shielding the blood vessel wall from immune and non-immune effectors of TAV. Our approach is based on our finding that the fate of the graft does not solely depend upon the host immune and non-immune effectors, but also on its ability to protect itself from injury. Our data suggest that this might be safely achieved by genetic engineering of the vessel wall with a single gene: A20. A20 is a physiologic protective response to injury in endothelial cells (EC) and smooth muscle cells (SMC), preventing TAV regardless of the precipitating offender. A20 is anti-inflammatory and anti-apoptotic in EC, and anti-inflammatory and anti-proliferative in SMC. Additionally, A20 sensitizes SMC to apoptosis. The conventional paradigm emphasizes the critical role of EC and SMC activation/proliferation in the progression of TAV lesions. Protection from TAV will best be achieved if we promote death of neointimal SMC while helping EC to survive. Our aim is to provide direct in vivo proof for the protective effect of A20 against TAV using A20 based gene therapy in rat aortic transplants.