**2. History of immunosuppression**

Early efforts at transplantation were unsuccessful because of inadequacies in surgical techniques and a fundamental lack of knowledge regarding the immune system. The development of immunosuppressive drug treatments enabled organ transplantation and improved the survival of transplanted organs since the first liver transplant by Dr. Thomas E. Starzl in 1963. Since then, many new and progressively more selective immunosuppressive agents and treatment strategies have been developed. As knowledge of the immune system evolved, therapies that targeted specific immunoregulatory organs enabled the ability to prolong life through organ transplantation. Initial attempts at immunosuppression were with total body radiation, but all of the patients died. In 1949, corticosteroids were used to treat autoimmune disorders and to prevent allograft rejection. Since then, many new and progressively more selective immunosuppressive agents have been developed. These therapies have enabled organ transplantation and improved the survival of transplanted organs. In 1959, cyclophosphamide was demonstrated to suppress antibody production and was used for bone marrow transplantation. In the 1960s, azathioprine (AZA) was found to delay organ graft rejection and was used to suppress the rejection of transplanted kidneys. The first polyclonal anti-lymphocyte globulin was used in 1967, and it spawned the development of other polyclonal and monoclonal antibodies for immunosuppressive therapy. After the first initially successful series of transplantations were performed between 1962 and 1964 in Denver, Colorado, the combination of azathioprine and steroids came into widespread use, becoming part of the primary immunosuppressive regimen for the next 20 years. The T cell-inhibiting properties of cyclosporine, a calcineurin inhibitor, were discovered in 1976. Subsequently, cyclosporine (Sandimmune and later, Neoral) was introduced in the 1980s, when it was used in combination with azathioprine and steroids to prevent rejection in allograft transplants. Its use was credited with a dramatic improvement in graft survival. In 1969, methotrexate was shown to inhibit antibody production and the development of delayed hypersensitivity in guinea pigs[5].

The development of mycophenolate mofetil (MMF), an inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, began in 1982, and research continues on other IMPDH inhibitors. Mycophenolate mofetil rapidly replaced azathioprine almost universally. The next advance occurred in 1987, with the introduction of tacrolimus (FK506) to inhibit interleukin (IL)-2 production and lymphocyte proliferation. Tacrolimus has gradually supplanted cyclosporine in many transplant centers. Interest in the antibiotic sirolimus (SRL), which is also known as rapamycin, was renewed in the 1980s when it was shown to prevent allograft rejection.

Other immunosuppressive agents and their dates of discovery include mizoribine in 1981, leflunomide in 1978, deoxyspergualin in 1981, muromab-CD3 (OKT3) in 1985, brequinar in 1986, azodicarbonamide in 1989, vitamin D analogs such as MC1288 in 1991, and bisindolylmaleimide VIII in 1999. Other agents that were developed include Minnesota antilymphocyte globulin and anti-thymocyte globulin (ATG)[6].

been discovered, where lower-than-conventional amounts of ongoing pharmacologic immunosuppression are needed[3, 4]. Although the induction of immunologic tolerance has been achieved and studied in numerous laboratory animal models, immune tolerance remains an elusive goal of transplantation immunology and clinical organ transplantation.

Early efforts at transplantation were unsuccessful because of inadequacies in surgical techniques and a fundamental lack of knowledge regarding the immune system. The development of immunosuppressive drug treatments enabled organ transplantation and improved the survival of transplanted organs since the first liver transplant by Dr. Thomas E. Starzl in 1963. Since then, many new and progressively more selective immunosuppressive agents and treatment strategies have been developed. As knowledge of the immune system evolved, therapies that targeted specific immunoregulatory organs enabled the ability to prolong life through organ transplantation. Initial attempts at immunosuppression were with total body radiation, but all of the patients died. In 1949, corticosteroids were used to treat autoimmune disorders and to prevent allograft rejection. Since then, many new and progressively more selective immunosuppressive agents have been developed. These therapies have enabled organ transplantation and improved the survival of transplanted organs. In 1959, cyclophosphamide was demonstrated to suppress antibody production and was used for bone marrow transplantation. In the 1960s, azathioprine (AZA) was found to delay organ graft rejection and was used to suppress the rejection of transplanted kidneys. The first polyclonal anti-lymphocyte globulin was used in 1967, and it spawned the development of other polyclonal and monoclonal antibodies for immunosuppressive therapy. After the first initially successful series of transplantations were performed between 1962 and 1964 in Denver, Colorado, the combination of azathioprine and steroids came into widespread use, becoming part of the primary immunosuppressive regimen for the next 20 years. The T cell-inhibiting properties of cyclosporine, a calcineurin inhibitor, were discovered in 1976. Subsequently, cyclosporine (Sandimmune and later, Neoral) was introduced in the 1980s, when it was used in combination with azathioprine and steroids to prevent rejection in allograft transplants. Its use was credited with a dramatic improvement in graft survival. In 1969, methotrexate was shown to inhibit antibody production and the

The development of mycophenolate mofetil (MMF), an inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, began in 1982, and research continues on other IMPDH inhibitors. Mycophenolate mofetil rapidly replaced azathioprine almost universally. The next advance occurred in 1987, with the introduction of tacrolimus (FK506) to inhibit interleukin (IL)-2 production and lymphocyte proliferation. Tacrolimus has gradually supplanted cyclosporine in many transplant centers. Interest in the antibiotic sirolimus (SRL), which is also known as rapamycin, was renewed in the 1980s when it was shown to

Other immunosuppressive agents and their dates of discovery include mizoribine in 1981, leflunomide in 1978, deoxyspergualin in 1981, muromab-CD3 (OKT3) in 1985, brequinar in 1986, azodicarbonamide in 1989, vitamin D analogs such as MC1288 in 1991, and bisindolylmaleimide VIII in 1999. Other agents that were developed include Minnesota anti-

**2. History of immunosuppression** 

development of delayed hypersensitivity in guinea pigs[5].

lymphocyte globulin and anti-thymocyte globulin (ATG)[6].

prevent allograft rejection.
