Over the past 50 years organ transplantation has become established worldwide with ever-improving results, conferring immense benefi t to hundreds of thousands of patients. The general principles of the surgical procedures and organ preservation have been accepted for all organ transplants, but the biology of graft rejection is still only partly understood. The discovery of natural acquired immunological tolerance and experimental methods of producing tolerance by Billingham, Brent, and Medawar raised the hopes of clinicians that there might be a way of inducing in the recipient at the time of organ grafting a state of temporary immunological plasticity similar to the stage that occurs in fetal development. In 1959 mercaptopurine, which is used in the treatment of leukaemia, was shown by Schwarz and Damechek to prevent antibody formation in rabbits challenged with foreign protein. They called this observation drug-induced immunological tolerance. Studies in the UK on kidney-grafted animals treated with mercaptopurine produced a moderate extension of graft survival and led to a practical clinical regimen of treatment with the mercaptopurine analogue azathioprine plus corticosteroids. At 1 year, graft function was around 50%. Kidney transplantation remained confi ned to about ten centres worldwide, and the procedure was viewed with suspicion because of the poor overall results. Then, in the late 1970s, Borel and colleagues discovered the immunosuppressive properties of the fungal cyclic peptide ciclosporin, which prolonged survival of skin grafts in mice. Further studies of this drug in the UK showed prolonged survival of cardiac allografts in rats and pigs and renal transplants in dogs. When ciclosporin was fi rst used in people, based on the dose given to animals, it was severely nephrotoxic. After a worrying learning curve of dose adjustments, ciclosporin was shown to improve the 1-year survival of kidney grafts to around 80%, and for the fi rst time surgeons became confi dent in transplanting the liver and heart with ciclosporin immunosuppression. Ciclosporin was a watershed in the development of transplantation. Instead of a treatment limited to a handful of centres worldwide, transplantation became a muchvalued form of therapy spreading to more than a thousand centres. The kidney was the organ most commonly transplanted, but increasingly good results were obtained with heart, liver, and, eventually, lungs and pancreas. One method of minimising the nephrotoxicity of ciclosporin was to combine this drug with azathioprine and corticosteroids so that the total immunosuppressive activity would be additive, but the individual side-eff ects of the diff erent agents would be less. Gradually, the “halflife” of organ transplants improved. Many new immunosuppressive agents have been investigated experimentally, and several have been introduced into the clinic, including polyclonal and monoclonal antilymphocyte antibodies. There has been an unfortunate tendency to add more and more potent immunosuppressive agents to therapy with concomitant over-immunosuppression. Bone-marrow transplantation has also advanced through new regimens of non-ablative transplantation with mixed chimaerism, initially planned to retain the graft-againstleukaemia eff ect but also used in an important series of clinical experiments in patients subsequently given kidney transplants, in whom tolerance occurred despite the disappearance of the donor chimaeric state in the blood. Besides their expense, conventional drug regimens can cause great hardship to patients and non-compliance is common. Some patients with liver transplants stopped taking their drugs and performed a clinical experiment demonstrating immunological tolerance, surviving many years with good liver function despite the absence of any maintenance immunosuppression. Other patients were not so lucky, and this weaning of maintenance immunosuppression is far more likely to be successful with liver than with kidney transplants, which is consistent with experimental demonstration of liver tolerance without any drugs after orthotopic liver transplantation in pigs and rodents. Lancet 2006; 368: S51–S52
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Jan 1, 2022
Darya A Alontseva + 4
Open Access