E arly mythology depicts two saints in a life-and- death struggle to save a limb from a foregone fate. Saints Cosmos and Damien replaced a cancerous leg with a limb from a deceased Moor. This illustration was mere fantasy until the latter part of the previous century with the seminal surgeries performed by Dr. Joseph Murray on identical twins and, later, Dr. Starzl's pioneering orthotopic liver transplant (OLT). Immunosuppression itself has come from the dark ages to where it stands today: a careful balancing act between toxicity and rejection. [1][2][3] This article is designed as an overview of current immunosuppression in OLT and will not delve into areas such as basic science or pipeline preview.
The first attempts at whole liver grafting were carried out in 1955 with auxiliary grafts. This involved insertion of an extra liver at an ectopic location. This approach left the diseased liver intact. Early results, however, were disappointing. This early experience in the animal model and later attempts in humans led to the development of the OLT model. This was first attempted in 1963 in humans and today is the primary model for liver transplantation. 4 Early immunosuppression was suboptimal at best. Corticosteroids and azathioprine were used in combination by Starzl et al. in his first 5 transplants. The majority of the Colorado series from 1963 to 1976 received corticosteroids, azathioprine, and antilymphocyte globulin. A total of 170 patients were transplanted, and approximately 50% were children. Patients were divided into 3 time-based series. Series 1 (1963-1976, 111 patients) had a 1-year survival rate of 28.8%, Series 2 (1976-1978, 30 patients) had a 1-year survival rate of 50%, and the Series 3 (1978-1979, 29 patients) had a 1-year survival rate of 34.5%. Variations on these approaches included thoracic duct drainage or cyclophosphamide, though neither produced significant advantage. The Cambridge University group reported on a series from 1968 to 1980 with a total of 93 patients, with a 1-year survival rate of 23.7%. The lower survival rate may have been due to the lower rate of pediatric patients transplanted by the Cambridge group. 5,6 This time frame has been referred to as the precyclosporine (CyA) era (Fig. 1).