Immunosuppressive Therapies in Organ Transplantation


June 25, 2002

In This Article

History of Immunosuppression

The model of renal transplantation has long been used in the investigation of the efficacy of current immunosuppressive regimens. Investigations that began in 1962 saw the use of azathioprine (AZA, Imuran) as the sole immunosuppressive agent.[1] There were few long-term survivors in these early trials, and eventually it was realized that cadaveric organ transplantation was not successful with AZA monotherapy.

In 1962 and 1963 it was demonstrated in renal transplant recipients that the combination of AZA and corticosteroids has additive and synergistic effects.[2] This double-therapy approach was soon adopted in several transplant centers and became the standard of therapy worldwide by 1964.[3,4,5] For more than a decade, however, the only satisfactory results were obtained in living-related donor transplants. The mortality and morbidity rates associated with cadaveric transplants were excessive, and the 1-year graft function rate was approximately 50%.[6] The addition of antilymphocyte globulin (ALG) as an adjunctive agent improved survival; however, the usefulness of ALG was eventually shown to be limited. Because of the inability to standardize the drug product, and the numerous associated side effects, ALG was used only as a short-term adjunct.[7]

Other variations of immunosuppressive regimens were subsequently examined, but none had a major impact on clinical transplantation. It was not until the late 1970s with the advent of cyclosporine (CsA) that the realm of immunosuppression began to change and newer immunosuppressive regimens were developed.

In 1976, Borel reported studies of a new immunosuppressive agent called cyclosporin A.[8] In 1979, the first major clinical experience with cyclosporin A was reported. Calne noted prolonged graft survival in his patient population when cyclosporin A was used as a single immunosuppressant regimen.[9] Until recently; however, the triple therapeutic approach of CsA, AZA, and corticosteroids was the preferred therapy for allograft transplantation. Triple-drug therapy will be discussed later in this chapter.

In the early 1980s, Cosimi began clinical trials using monoclonal antibodies against mature T lymphocytes.[10] Soon afterward, other studies demonstrated that intractable rejection of renal grafts could be reversed with monoclonal antibodies.[11,12] In 1987, the monoclonal antibody CD-3 was approved by the Food and Drug Administration and marketed as Orthoclone OKT-3.