Essay History of transplantation

Roy Calne Lancet 2006; 368: S51–S52

Over the past 50 years organ transplantation has become
established worldwide with ever-improving results,
conferring immense benefit 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 confined 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
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 The printed
an unfortunate tendency to add more and more journal
potent immunosuppressive agents to therapy with
includes an
concomitant over-immunosuppression. Bone-marrow
transplantation has also advanced through new image merely
regimens of non-ablative transplantation with mixed for illustration
chimaerism, initially planned to retain the graft-against-
leukaemia effect but also used in an important series of
clinical experiments in patients subsequently given
kidney transplants, in whom tolerance occurred despite Sir Roy Calne developed an
the disappearance of the donor chimaeric state in the internationally renowned kidney
and liver transplant programme
blood. at Addenbrooke’s Hospital,
Besides their expense, conventional drug regimens Cambridge, after being
can cause great hardship to patients and non-compliance appointed Professor of Surgery
in the University of Cambridge in
is common. Some patients with liver transplants stopped
1965. He was elected Fellow of
taking their drugs and performed a clinical experiment the Royal Society in 1974 and
demonstrating immunological tolerance, surviving was knighted by the Queen in
many years with good liver function despite the absence 1986.
of any maintenance immunosuppression. Other Department of Surgery,
patients were not so lucky, and this weaning of main- Douglas House Annexe,
18 Trumpington Road,
tenance immunosuppression is far more likely to be Cambridge CB2 2AH, UK
successful with liver than with kidney transplants, (Sir Roy Calne FRS)
which is consistent with experimental demonstration of Correspondence to:
liver tolerance without any drugs after orthotopic liver Sir Roy Calne
transplantation in pigs and rodents. cpr1000@cam.ac.uk

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 first 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 first time surgeons became
confident 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 much-
valued 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-effects of
the different agents would be less. Gradually, the “half-
life” of organ transplants improved. Painting of a transplantation operation by Sir Roy Calne

www.thelancet.com Medicine and Creativity Vol 368 December 2006 S51


Historical landmarks in transplantation
1943 Description of skin graft rejection as an immune process
1951 Natural and experimental tolerance
1954 First successful clinical kidney transplant between identical twins
1959 Inhibition of antibody production in experiments with mercaptopurine
1960 Prolongation of survival of experimental kidney transplants by mercaptopurine
1961 Prolongation of survival of experimental kidney transplants by azathioprine
1962 Use of azathioprine and steroids in clinical renal transplants
1963 First clinical liver transplant
1967 First clinical heart transplant
1978 Use of ciclosporin in clinical renal transplants
1981 Use of monoclonal antibodies to lymphocytes in organ grafting
1989 Use of tacrolimus in clinical organ grafts
1995 Use of sirolimus in clinical organ grafts
1998 Alemtuzumab induction and low-dose maintenance immunosuppression in
clinical renal transplants
From the patient’s point of view, minimal immuno-
suppression without obvious side-effects is an attractive
proposal compared with conventional immuno-
suppression. This approach has been called “almost or
prope tolerance” and was first used with the powerful
lympholytic monoclonal antibody Campath 1H
(alemtuzumab). 5-year follow-up of the first renal-
transplant recipients treated with alemtuzumab induction
and maintenance low-dose ciclosporin has shown
satisfactory results.
There is now much experience of the use of induction
followed by steroid-free maintenance immuno-
suppression, and this approach seems likely to become a
favoured method of recipient management for all organ
grafts except in patients with active viral infections, which
can be exacerbated by alemtuzumab.
When I first started working on research in organ
transplantation in 1959, I had no idea of the great
importance that ethical and legal considerations would
assume. I had imagined that when we overcame
rejection and learned how to do the surgery, good results
Further reading would eventually be achieved in organ grafts taken from
Groth CG, Brent LB, Calne RY, cadaver donors. Now, however, matters have changed,
et al. Historic landmarks in
largely because the success of transplantation has
clinical transplantation:
conclusions from the consensus increased the demand for organs. Whenever something
conference at the University of is wanted but in short supply, there will be pressure to
California, Los Angeles. World J obtain the commodity by payment. Organ transplants
Surg 2000; 24: 834–43.
from animals were proposed as the solution; advances
Moore FD. Transplant: the give have occurred, but the clinical application still seems to
and take of tissue
transplantation. New York:
be a long way off. There has been much discussion
Simon and Schuster, 1972. about the payment of donors for organs, whether the
Starzl T. The puzzle people: donor or his or her family should be paid directly or
memoirs of a transplant surgeon. through a government agency, or whether payment
Pittsburgh: University of should be forbidden, in which case there is a danger of
Pittsburgh Press, 1992.
illicit payment or other means of coercion. Certainly,
Calne R. The ultimate gift: the
there is very little precedent for organ donation from the
story of Britain’s premier
transplant surgeon. London: rich to the poor; it is in nearly all cases in the other
Headline, 1998. direction. There seems to have been serious abuse in
S52
some developing countries. In some countries where
capital punishment is practised, organ donation from
prisoners has been widespread; the details are seldom
published, but many patients from countries where this
practice is not permitted travel as organ-transplant
recipients on “package deals” to receive organ grafts.
The practice has been outlawed by the Transplantation
Society but has not stopped.
In developed countries there is an increasing tendency
to undertake organ transplantation from living donors.
The argument for transplantation between identical
twins seems to be generally acceptable and sanctioned by
law. Similar feelings are generally expressed for
transplantation between adult siblings and from parents
to children. Now, however, there are many cases of
transplantation between people who are not blood
relatives, between spouses and even totally unrelated
friends. In some centres, the onus of finding a donor is
put onto the patient, who is expected to find a family
donor, perhaps even their own child, or a generous
benefactor. It is difficult for the doctor to explain and for
the potential donor to understand the dangers of organ
donation and the fact that the result might be a failure,
either surgical or immunological. There is always a
danger to the donor for kidney donation; the mortality is
in the region of one or two per 1000. For liver donation,
the morbidity to the donor of an adult half liver can be as
high as 40% with a risk of death of 1–2%. Some
unreported deaths have occurred in transplants done by
itinerant surgeons in centres lacking the expensive
infrastructure needed for this major complicated surgery.
Many of us believe that this is an unacceptable risk to
confront a perfectly healthy person, who may not even be
an emotionally related or blood relative. The potential
donors may feel an obligation or, if they refuse, or the
family is against the operation, they may feel guilty if the
person in need of transplantation dies. In the UK, only
50–60% of the population will give permission for organ
donation after death. The concept of brain death is hard
to explain to medical students, so not surprisingly is even
more difficult to explain to non-medical individuals.
The actual practice of organ transplantation is viewed
differently according to whether the transplant team are
paid individually for each operation, as is the case for
both donor and recipient teams in some centres in the
USA, but does not apply in most European countries.
The donor team have to be available at all times, often for
long journeys, frequently at night, to a centre where their
presence is not exactly welcomed.
The removal of organs from a person who has died
tragically is always a sad business. There is therefore a
shortage of transplant surgeons in some countries,
especially now that the operations are routine and there
is little room for surgical improvement. I suspect that
these matters will be among the most important
challenges in organ transplantation for the future—a
consequence of the success of the procedure.
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