**2. Evolution of immunosuppression**

Rejection of the transplant remained a major problem until cyclosporine-A was discovered by Jean Borel.[33] The 1-year survival rate following liver transplantation was 30% to 50% prior to the discovery of cyclosporine-A,[34,35] however, after the introduction of cyclosporine-A, the 1-year and 3-year survival rates were 74% and 67% in the first 1000 recipients treated with cyclosporine-A at the University of Pittsburgh in the early 1980s.[36] After these good results, growth of liver transplantation was facilitated by the conclusion of the National Institute of Health Consensus Development Conference in 1983 that liver transplantation is not an experimental procedure but an effective therapy that deserves broader application.[34] Shortly thereafter, the first monoclonal antibody OKT3 was discovered by Cosimi in 1981 and proved effective in treating acute transplant rejection and was sometimes used along with cyclosporine-A based regimen as immunoprophylaxis especially in North American Centers or to treat steroid resistant graft rejection.[37] Since then, many new immunosuppressive agents were introduced. In 1990, Mycophenolate mofetil (MMF, CellCept) was introduced by University of Wisconsin and proved, in combination with cyclosporine-A, to further reduce the incidence of graft rejection episodes better than azathioprine with less toxic effects.[38] In the same year, Rapamycin (Sirolimus) was introduced.[39] It is like cyclosporine-A but it has a different mechanism of action. It inhibits lymphocyte proliferation through prevention of ligation of IL-2 to the IL-2 receptors.[40] In 1994, Ochiai in Japan introduced tacrolimus (FK506, Prograf) and proved to reduce the incidence of transplant rejection more than cyclosporine A. It is like cyclosporine-A but hundred times more potent and is indicated in severe acute rejection resistant to standard immunosuppressive protocols and in chronic rejection.[41]

Greater understanding of the underlying liver disease, improved surgical and anaesthetic techniques, reliable immunosuppression and dependable postoperative care over the last few years have contributed towards improved results of liver transplantation. This success has resulted in a disproportionate increase in demand of liver transplantation and the appearance of a major problem of shortage of available donor organs, leading to a prolonged waiting times and high mortality on the waiting list.[42]

#### **3. The progress in liver transplantation with donor shortage**

The donor shortage together with the development of surgical skills of liver resections based on the knowledge of segmental anatomy of the liver described by Couinaud,[43] opened the door for innovative methods of transplantation including auxiliary liver transplantation, reduced-liver transplantation (RLT), split liver transplantation (SLT) and living donor liver transplantation (LDLT).[44,45] Also, The donor shortage had led to the evolution of hepatocyte and stem cells transplantation which will be the future in the liver transplantation.
