Organ Transplantation Has come of Age

Abstract

Organ transplantation started in the mid-1950s with a kidney transplant between identical twins, demonstrating the surgical technique could provide successful therapy. The immunological barrier to be overcome, however proved to be far more difficult to deal with. The introduction of immunosuppressive agents produced some success but it was not until Cyclosporin became available in the 1980s that results became sufficiently good for widespread acceptance and rapid development of organ grafting. Now with more powerful and selective agents, although there is still much room for improvement in immunosuppression, one of the main problems in organ transplantation is a result of its success, namely a shortage of organ donors. In this review, I summarise these matters.

Full text

Organ transplantation has come of age
ROY Y. CALNE
ABSTRACT
Organ transplantation started in the mid-1950s with a kidney transplant
between identical twins, demonstrating the surgical technique could provide
successful therapy. The immunological barrier to be overcome, however, proved
to be far more difficult to deal with. The introduction of immunosuppressive
agents produced some success but it was not until Cyclosporin became
available in the 1980s that results became sufficiently good for widespread
acceptance and rapid development of organ grafting. Now with more powerful
and selective agents, although there is still much room for improvement in
immunosuppression, one of the main problems in organ transplantation is a
result of its success, namely a shortage of organ donors. In this review, I
summarise these matters.
Keywords:organ transplantation, immunosuppression, donor shortage
Roy Yorke Calne was born in 1930 in Surrey, educated at
Lancing College and received his medical training at
Guy’s Hospital in London. After doing his National
Service in Hong Kong, Singapore and Malaysia, he held
surgical appointments at a number of London hospitals
and at Harvard Medical School. He developed an inter-
nationally renowned kidney and liver transplant pro-
gramme at Addenbrooke’s Hospital Cambridge after
being appointed Professor of Surgery in the University
of Cambridge in 1965. He was elected Fellow of the
Royal Society in 1974 and was knighted by the Queen in
1986. Sir Roy Calne is the foremost pioneer of liver transplantation in the UK, a
speciality he pursued when the overwhelming thinking in medical circles was that
it could not be done. Although the surgical techniques involved are very complex,
it is the issue of rejection that has caused the greatest problems. Sir Roy was the
first to use drugs to control the body’s natural rejection of donated organs and this
major breakthrough produced an enormous expansion in the transplantation
programme. Sir Roy retired from his chair at Addenbrooke’s Hospital in 1998
and lives with his wife in Cambridge where he has a private office. He is
Emeritus Professor in Cambridge and Visiting Professor of Surgery to the
National University of Singapore. E-mail: calne@hermes.cam.ac.uk
Science Progress (2010), 93(2), 141–150
doi: 10.3184/003685010X12708274571283
www.scienceprogress.co.uk 141

Introduction
Organ transplantation did not exist as clinical therapy until the mid
1950s yet in the intervening years it has developed at a remarkable
rate from a procedure considered to be dangerous and irresponsible
to a ‘‘gift of life’’ to around a million people, who were otherwise
doomed due to untreatable and fatal disease of vital organs. In the
last few months, more than 10,000 health care workers have
attended two international meetings on organ transplantation, one
in Boston and one in Paris and although the pace of scientific
advance has slackened there are still many problems to be over-
come, the greatest is to find enough organs for patients in need.
This is a malady resulting from the success of organ transplantation.
I will consider three aspects of organ transplantation, namely the
technique, the immunological barriers, and the ethical dilemmas.
Technique
The early work on the science of transplantation was performed
with skin grafts. Techniques have been available for centuries for
grafting using a flap or free-grafting using very thin slices of the
skin. In both techniques, development and maintenance of the blood
supply of the graft is essential. In a flap graft, some blood vessels
are preserved; in a free graft, new vessels have to grow into the
living tissue, which is extremely vulnerable until vascularisation is
established, since nourishment depends solely on diffusion of vital
materials to the graft and removal of waste products from the graft.
Once blood vessels are established the graft is robustly viable but
becomes subject to immunological rejection. The classical studies
by Medawar and his colleagues in the 1940s, showed that rejection
was an active immunological process, involving an ‘‘immunological
memory’’ similar to that which develops after an infectious disease,
so that a second graft from the same donor to the same recipient
was rejected much more quickly than the first
1
.
A method of overcoming graft rejection was observed in skin
grafts performed between non-identical cattle twins by Medawar’s
group who found to their surprise that the grafts were not rejected
2
.
Subsequently an explanation of this phenomenon of ‘‘natural
immunological tolerance’’ was attributed to the unusual cross-
circulation of blood in the placenta of non-identical cattle twins,
which seldom occurs in other species. Thus the plasticity of the
immune system during embryological development became a
subject for study. Following up on their observations in the cattle
142 Roy Y. Calne

twins Medawar’s group found that injection of cells experimentally
from an inbred strain of mice into a different strain during
embryonic development by intra-uterine or neonatal injection
resulted in graft acceptance for prolonged periods but not always
indefinitely
3
.
An important complication of this procedure was observed by
Billingham and Brent, namely a wasting disease known as ‘‘graft-
versus-host’’ disease in which the injected cells, if they were
immunologically competent, could destroy the host
4
.
This is an important consideration in any attempts at therapeutic
tolerance in which immunologically active cells are used as a
vehicle to promote tolerance.
At the time when these experiments were being performed
Dempster and Simonsen were investigating the fate of kidney
grafts, having developed a surgical technique that restored the
arterial inflow and venous outflow of the grafted kidney
5,6
.
Provided the surgery was performed accurately and swiftly, the
kidney could withstand the period without a blood supply during
the transfer operation. As with skin, severe destructive rejection was
observed usually between 7 and 10 days. The histology revealed
dense infiltration of the graft with lymphocytes and plasma cells,
which suggested that a cellular immune mechanism and antibody
formation were both contributing to the destruction of the graft.
Further studies of the techniques of kidney grafting and the
demonstration of an extra peritoneal site for grafting the kidney
with urine drainage directly into the bladder, introduced by Kuss in
Paris
7
, removed the surgical barriers to kidney transplantation. A
surgically satisfactory operation for the patient was demonstrated in
clinical application demonstrated by Murray and his colleagues in
1955 in the special situation where the donor and recipient were
identical twins derived from the same egg
8
.
They recognised each other’s tissues as identical and ‘‘self’’ and
therefore there could be no immunological rejection. The success of
the early identical twin transplants at the Peter Brent Bingham
Hospital raised the hopes of surgeons and physicians that trans-
plantation of kidneys between donors and recipients who were not
identical twins might be possible. The first technique to prevent
rejection that was tried in the clinic was total body X-irradiation.
This can be very toxic but in two patients receiving kidney grafts
from non-identical twins of identical tissue types, success was
achieved using this method in Boston
9
and in Paris
10
. Extreme
disappointment followed the use of this treatment in situations
where the donor and recipient were not closely related.
www.scienceprogress.co.uk Organ transplantation has come of age 143

During the 1960s surgical techniques were developed for trans-
plantation of heart, liver, lungs and the pancreas. There was a huge
literature of debate amongst surgeons, but this gradually subsided as
there developed a consensus of agreement as to how each organ
should be transplanted from a surgical point of view. Controversy
has re-awakened in the last few years with the use of living donor
liver transplants, where a portion of the liver is used as the graft that
must provide sufficient liver function for the recipient but also not
remove too much liver from the donor. Details of the minutiae of
the surgical procedure for such operations are still being debated.
Organ preservation
Deprived of its blood supply an organ will rapidly deteriorate but
the speed of deterioration is closely related to the temperature of the
organ. Using the principle of a refrigerator, it was found that
cooling of organs, both by immersing in a cold, melting ice
environment, and also perfusing cold, non-damaging solutions
through the vasculature of the organ, successful preservation of
kidneys for 24 hours could be achieved. Other organs are more
vulnerable, heart and liver can tolerate ischaemia for only a few
hours before irreversible damage occurs. Other attempts at organ
preservation relied on perfusing the organ with oxygenated blood or
blood products, cooled or at body temperature. Such perfusion
apparatus requires constant monitoring as there are many sites in the
mechanical circuit that can, and often do, go wrong. Machine
preservation of the kidney can extend the safe period of ischaemia
to 36 or even 48 hours, certainly time to move the organ, long
distances or even intercontinentally by air.
Rejection and immunosuppression
X-irradiation was most successful for bone marrow transplantation
for blood diseases. The principle was to subject patients to high
doses of total body X-irradiation, to destroy the immune system
completely and then replace the immune system with bone marrow
aspirated from the donor. This approach has transformed the
treatment of many malignant and non-malignant blood diseases.
As might be expected, the bone marrow with potentially active,
immunologically competent cells can and often does react against
the recipient, producing a ‘‘graft-versus-host’’ disease which can be
lethal but also may be helpful in the cases of leukaemia where the
graft-versus-leukaemia conflict can help in the therapy for the
144 Roy Y. Calne

patient. The results of bone marrow transplantation are closely
related to the tissue matching of donor and recipient. Not only
must the blood group be compatible but also the tissue groups.
Tissue typing developed in the 1950s and required a great deal of
work and collaboration of different laboratories to get an agreement
on classification, nomenclature and technical details. The so called
histocompatibility tissue types are very complicated, the deter-
mining genes in man are situated on chromosome 6. Tissue
typing between siblings follows Mendelian laws so there is a 1 in
4 chance of identity, 2 in 4 chances of a half match and a 1 in 4
chance of a complete mismatch. The chance of unrelated pairs
having an identical match is dependent on the incidence of the
different tissue antigens in the population but, in general, a random
testing of unrelated individuals is unlikely to give complete match.
However, when large populations are tested the recorded tissue type
can be used to identify volunteer donors of bone marrow from
around the world who may be able to help an individual suffering
from a lethal blood disease. In the last 15 years, there have been
considerable advances in bone marrow transplantation. In particular,
the very harsh immunosuppression needed to destroy completely
the patient’s immune system can often be reduced to a less severe
regimen, better tolerated by the patient, this is called the ‘‘non
ablative’’ immunosuppression for bone marrow transplantation
11
.
Using this technique interesting results were reported by workers at
the Massachusetts General Hospital, for patients suffering from
malignant myeloma and renal failure
12
. They were treated with a
bone marrow transplantation from an HLA identical sibling and
then subsequently a kidney transplant from the same sibling. Some
of these patients achieved complete tolerance in that they did not
require maintenance immunosuppression and have survived long
periods without rejecting their renal grafts. Good results were also
reported by the same group when there was one haplotype
mismatch between donor and recipient
13
.
For organ transplants, total body irradiation in general is unsa-
tisfactory, but the use of powerful anti-leukaemic drugs was shown
to prolong renal allograft survival in experimental animals, in
particular 6-mercaptopurine and its derivative Aziothioprine were
the first immunosuppressive agents which, together with systemic
corticosteroids, provided a platform for clinical renal transplanta-
tion
14,15
. Results, although not good, were certainly an improve-
ment on total body irradiation. Some 50% of patients with grafts
from unrelated donors had good graft function at one year, and
some of those patients have survived for very long periods. Clinical
www.scienceprogress.co.uk Organ transplantation has come of age 145

organ transplantation, however, remained an experimental proce-
dure, much criticised by many members of the medical profession
because of the poor results. The introduction of the calcinurin
inhibitor, Cyclosporin, as an immunosuppressant raised the func-
tional survival of kidney grafts from 50% at one year to over 80%
and was a watershed in the perception of the procedure of organ
grafting
16,17
. In the next few years, organ grafting became estab-
lished and accepted and good results were obtained with transplants
of liver, heart, lung and pancreas. One serious side effect of
Cyclosporin, not observed in any of the pre-clinical experiments,
was the tendency in patients to develop renal damage as a result of
the drug’s nephrotoxic effects. Similar nephrotoxicity was observed
with another calcinurin inhibitor, Tacrolimus, which is now the
most widely-used calcinurin inhibitor, because its other side effects
are usually less than those of Cyclosporin. There were efforts
worldwide to find new immunosuppressive agents with better
therapeutic indices than calcinurin inhibitors. Especially promising
were biological agents, namely antibodies produced against human
lymphocytes or thymocytes. The polyclonal versions of anti-
lymphocyte preparations were difficult to standardise, but in the
last 20 years following the demonstration of monoclonal antibodies
with a single molecular target, new antibodies have been used in the
clinic with more predictable results and good efficacy.
Aziothioprine and mycophenolate which have similar anti-prolif-
erative actions were added to the calcinurin inhibitors and steroids.
In addition, some transplant centres used a poly- or monoclonal
antibody at the time of transplantation as an induction agent.
Unfortunately, there was a tendency to add agents that were
effective to already established regimens, often resulting in over-
immunosuppression and probably preventing any tendency that the
body might develop tolerance spontaneously. When an immune
reaction is initiated there needs to be a method of switching it off
when it is no longer needed and this should in theory result in
tolerance in an adult patient. In fact, a number of liver transplant
patients themselves ‘‘conducted experiments’’ by stopping immu-
nosuppression without telling their doctors. Some of them have
survived up to 30 years without any need for immunosuppression
18
.
This is especially a feature of liver transplants and would suggest
that in man, as in experimental animals particularly pigs and
rodents, liver transplants are less likely to be rejected destructively
than grafts or other organs
19
. The reason for this is not known but
there is a hierarchy of susceptibility to rejection with liver being at
one end and skin and intestine being most likely to be rejected.
146 Roy Y. Calne

In the past few years, the counter-productive results of over-
immunosuppression have been recognised and there is now a
tendency worldwide to develop protocols in which minimal main-
tenance immunosuppression is the objective. A particularly
powerful monoclonal antibody developed in Cambridge, Campath
1H, which destroys very rapidly all lymphocytes circulating in the
blood, has been used as an induction agent in kidney grafting at the
time of the operation. The patient is then maintained on half dose of
Cyclosporin and no other immunosuppression, instead of full dose
of three or more drugs. This regimen does not produce tolerance,
but has advantages over many previous therapeutic strategies and
has been called ‘‘almost or prope tolerance’’
20
. It would seem to be
the best that we currently have to offer our patients, since the
maintenance immunosuppression is usually below the threshold of
serious drug side effects, particularly nephrotoxicity.
Further developments of this approach with other agents are to be
expected in the future. So, now we can expect the half-life for vital
organ grafts of all types of around 10 to 14 years depending on
recipient and donor characteristics and also immunosuppressive
protocols. This has resulted in a serious shortage of organ donors,
because the good results widen the criteria of recipient selection and
increase the gap between the number of organs available and the
potential recipients on the waiting lists.
Ethical matters
In the last few years, the ethical worries of organ transplantation
have become prominent and have been discussed at length by
healthcare workers, politicians and patients. When a treatment is
available there is a tendency to feel that it should be provided for all
in need, but this is just not possible for organ transplants. The
source of organ donation is from dead patients, where the organs
are removed immediately after death, or organs or parts of organs
donated by volunteers. In some countries, organ donation is
extremely well developed and accepted by the public. The prime
example being Spain where the law permits the removal of organs
after death provided no objection has been made by the patient in
his or her life time. The value of this ‘‘opting-out’’ law compared
with the more conventional voluntary ‘‘opting in’’ continues to be
debated, but in Singapore the introduction of an ‘‘opting-out’’ law
resulted in a 10-fold increase in the number of deceased organ
donations.
www.scienceprogress.co.uk Organ transplantation has come of age 147

A living volunteer donor can give a kidney, half a liver or even a
lobe of the lung but before organ grafting it was unprecedented to
harm a normal healthy individual. The gross shortage of organs for
transplantation has put pressure on individuals to donate. Within a
family for a parent to donate a kidney or part of a liver to a child
would seem to be acceptable. There is a danger in any operation
and even kidney donors have suffered morbidity and occasional
mortality. With liver donors the risks are much greater, particularly
taking half of a liver from an adult to treat an adult with liver
failure. There have been cases where the recipient has had
insufficient liver but even worse where the donor has died from
liver failure.
It is not surprising that with such a valuable commodity as a life-
saving organ that is far more important to the suffering patient than
any wealth, power or temporal favours, that the gift of an organ is
literally a ‘‘gift of life’’ and the means to obtain an organ when one
is not obviously available puts stress on conventional moral values.
A rich person may travel to a poor country to pay for an organ from
an impoverished donor or from a criminal subjected to capital
punishment. There have even been rumours of people abducted and
their organs removed by criminal gangs, leaving the unwilling
donor without a kidney or even worse dead. This background has
caused great distress to all those involved in organ transplantation
and has raised the question of whether all patients who might
benefit from an organ deserve to get a graft. Should those suffering
from alcoholic liver disease or self-induced drug abuse receive a
transplant? Should there be an age threshold? And there are serious
considerations concerning the quality of organs that are offered, the
age and health of the donor. All these matters have become a main
concern for transplanters. If immunosuppression is improved and
long-term survival increased then there would be less organ graft
failure from rejection and less of a need to re-transplant patients
who have rejected their grafts, so there would be more donor organs
available, but the improved results would increase the demand for
organ grafting.
As mentioned at the beginning of this article the ethical
dilemmas are great and will increase as results of transplantation
improve. It behoves the transplant community to be concerned
about these matters, even if overcoming all the ethical worries is
probably impossible, at least defining and discussing them is the
first step in improving the ethical scenario in which transplants are
performed.
148 Roy Y. Calne

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