What has been the evolution of immunosuppression therapy after solid organ transplantation?

Updated: Jan 04, 2016
  • Author: Bethany Pellegrino, MD; Chief Editor: Mary C Mancini, MD, PhD, MMM  more...
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The ability to prolong life by transplanting organs had long been a dream of medical practitioners. Early efforts at transplantation were unsuccessful because of inadequacies in surgical technique and lack of fundamental knowledge of the immune system.

Skin and eyes were among the first successful transplants. However, the more complex organs posed countless problems. The kidney was the first such organ to be successfully transplanted. Surgical techniques progressed with the unsuccessful attempt at transplanting a cadaveric kidney in 1933. Initial attempts at immunosuppression were with total body radiation, but all the patients died. Steroids alone were then used, also without success.

With the development of 6-mercaptopurine (Purinethol), followed by azathioprine (Imuran) in the early 1960s, pharmacological immunosuppression became the standard of care. In the early 1960s, 2 major breakthroughs finally addressed the rejection problem. Beginning in 1962, it became possible to closely match donor and recipient tissue. After the first initially successful series of transplantations performed between 1962 and 1964, the combination of azathioprine and steroids came into widespread use and became part of the primary immunosuppressive regimen for the next 20 years. The first human pancreas transplantation was performed in 1966.

As knowledge of the immune system evolved, therapy targeted to specific immunoregulatory sites became possible. The first polyclonal antilymphocyte globulin was used in 1967 and spawned the development of other polyclonal and monoclonal antibodies. Introduced in the 1980s, cyclosporine (Sandimmune and, later, Neoral), a calcineurin inhibitor, was used in combination with azathioprine and steroids and was credited with a dramatic improvement in graft survival. Cyclosporine greatly improved the outcome of such transplants. The first successful heart-lung transplant was carried out in 1981.

The next advance came in 1994 with the introduction of mycophenolate mofetil (CellCept). After tacrolimus (another calcineurin inhibitor) became available in 1994, debate followed regarding which calcineurin inhibitor was superior. Tacrolimus has gradually supplanted cyclosporine in many centers. In contrast, mycophenolate mofetil rapidly replaced azathioprine almost universally. To expand the armamentarium further, sirolimus (Rapamune), a macrolide antibiotic, was developed and released.

While the short-term outcomes provided with these medications have continued to improve, the consequences of their administration have become the subject of intense scrutiny as comorbid conditions, drug toxicities, and adverse effects keenly affect both patient and graft survival.

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