Transplantation tolerance by donor MHC gene transfer

Replacing the function of diseased organs by transplantation has proved to be highly successful in the past four decades. The immune system poses the most significant barrier to the long term survival of the transplanted organs. Without lifelong treatment with powerful immunosuppressive agents to keep the immune response at bay, organ grafts will invariably be rejected. However, current immunosuppressive agents are non-specific and leave transplant recipients more susceptible to opportunistic infections and tumour development. Achieving donor specific tolerance would eliminate the need for lifelong treatment with these agents and thereby, avoid the associated side effects. There have been many exciting new developments in immunopharmacology and in the understanding of the mechanisms of rejection and tolerance. These developments on their own, or in combination with the use of gene therapy techniques may allow the induction of transplantation tolerance in human recipients of allografts in the future. Pretransplant exposure to donor MHC antigens has been highly successful strategy for tolerance induction in experimental models. Pretransplant blood transfusion, and more recently administration of donor bone marrow, has been used in an attempt to prolong graft survival in human. However, using fully allogeneic donor bone marrow carries the risk of graft versus host disease. Gene therapy may allow this approach to be used without this risk. Here, we review efforts to induce transplantation tolerance by gene transfer of donor MHC genes to recipient derived cells and show that this may be a potential strategy to achieve the holy grail of organ transplantation: donor specific tolerance.