- Dr. Miguel P. Soares, Principal Investigator
- Prof. Fritz Bach, Co-Investigator
- Harvard Medical School, Boston, USA
- Mechanisms of action of protective genes that promote organ graft survival
Organ allotransplantation is among the important medical advances of this century. However, the success of this approach has created a new problem: the shortage of donor organs available for this procedure. Based on this consideration, xenotransplantation of pig organs into humans is considered as a potential solution. The major obstacle to the clinical applications of xenotransplantation is that porcine organs are always rejected when transplanted into primates. In our center we use as an experimental model to study the mechanisms involved in xenograft rejection the transplantation of mouse hearts into rats. We have recently developed an immunosupressive treatment that allows such xenografts to survive indefinitely. This grant is based on the new finding, by our group, that mouse to rat cardiac xenografts that survive indefinitely under this immunosuppressive protocol protect themselves against rejection. The mechanism underlining this phenomenon relies on the expression, by endothelial cell (EC) lining the surface of xenograft blood vessels, of a series of "protective genes". These genes protect EC from dying and in addition inhibit the expression of pro-inflammatory genes that presumably contribute to xenograft rejection. We will study one of such protective genes, heme-oxygenase-1 (HO-1), the expression of which we have shown to be essential to insure the survival of mouse hearts transplanted into rats. One of the main goals of this proposal is to analyze the cellular/molecular mechanisms by which expression of HO-1 in EC protects mouse to rat cardiac xenograft from being rejected. The other main goal is to analyze whether the transgenic overexpression of HO-1 in the xenograft endothelium would prevent the rejection of mouse to rat cardiac xenografts, under conditions leading to the rejection of non-transgenic grafts. We believe that the results gained in this application will provide innovative new approaches to overcome xenograft rejection in a clinically relevant situation such as in pig organs transplanted into primates.