The dream of the ancients from time immemorial has been the junction
of portions of different individuals, not only to counteract disease,
but also to combine the potentials of different species. This desire
inspired the birth of many mythical creatures which were purported to
have capabilities normally beyond the power of a single species. The
modern world has inherited these dreams in the form of the sphinx, the
mermaid and the chimerical forms of many heraldic beasts.
Christiaan Barnard, 1967
Background
Transplantation, which is the transfer of organs, cells, and tissues
from one location to another, began many centuries ago as a primitive
practice and has since evolved into a modern reality. Modern medicine
has triumphed over many challenges and overcome many hurdles to achieve
successful organ transplantation. The contemporary practice of medicine
includes transplantation of tissues, partial organs, and whole organs.
In addition, successful bone, heart valve, cartilage, vein, and cornea
transplantations are being performed on a daily basis.
Transplantation can be characterized according to either the genetic
relationship between the donor and recipient or the anatomical site of
the implantation. The genetic relationship is characterized into 4
classes. In an autograft, the donor and recipient is the same
individual. In an isograft or syngeneic graft, the donor and recipient
are genetically identical (eg, monozygotic twins). In an allograft or
homograft, the donor and recipient are genetically unrelated but belong
to the same species. In a xenograft or heterograft, the donor and
recipient belong to different species.
Based on the site of implantation, the transplantation can be
described as orthotropic or heterotropic. Orthotopic transplantation
refers to donor tissue implanted in the anatomically correct position in
the recipient; heterotopic transplantation refers to the relocation of
the implant in the recipient at a site different from the normal
anatomy.
Prehistory
Mythologic tales of chimeric beings have been told all over the
world, although these transplantations were by supernatural forces
rather than by surgical methods. The earliest evidence of an orthotopic
autograft has been preserved from the Bronze Age. A circular disk of
bone was removed from the calvarium to relieve intracranial pressure and
later replaced as an autograft. Written accounts from Egypt, China, and
India dating back many centuries describe experimentation in grafting.
One Indian text from 700 CE describes a procedure for nasal
reconstruction that is very similar to modern methods.
Dawn of modern transplantation
The reality of organ transplantation began with advances in chemical
anesthesia and aseptic surgery. In 1540, the alchemist Valerius Cordus
synthesized ether and observed its effects on animals. The use of ether
for surgery and dentistry became widespread in the mid 1800s. Joseph
Lister pioneered the field of aseptic surgery based on Louis Pasteur’s
advancement of bacteriology.
Alexis Carrel is known as the founding father of experimental organ
transplantation because of his pioneering work with vascular techniques.
The work of Carrel and Charles Guthrie described in The
Transplantation of Veins and Organs served as the foundation of
vascular surgery and organ transplantation. An organ perfusion system
created by Carrel and Charles Lindbergh led to the development of
cardiopulmonary bypass by John Gibbon, thus making open heart surgery a
reality.
Frank Mann studied renal and heart transplantation at the Mayo Clinic
in the 1930s. Early transplantation attempts in humans, which began with
transplantation of renal allografts in 1936, generally did not succeed
until the discovery of immunogenetics and the implementation of
immunosuppressive drugs.
Evolution of organ donation and procurement
In the early 1960s, cadaveric donations were thought to be
impractical and impossible. Living donors were the only available source
of organs for transplantation. At Massachusetts General Hospital, a
liver was harvested from a police officer whose heart was beating but
whose brain was deemed dead. This seminal event led to the development
of the concept of brain death as death, rather than the cessation of
circulation, which previously defined death. The concept of brain death
greatly increased the number of organs available for donation and
improved the preservation of harvested organs. Once the concept of brain
death was established, a system for organ procurement was founded to
ensure the quality and availability of organs as efficiently as
possible.
National Transplant Act
In 1984, the US Congress passed the National Transplant Act, which
prohibited the sale of organs for transplantation. The nationwide
sharing system known as the Organ Procurement and Transplantation
Network, which was subsequently contracted to the United Network for
Organ Sharing, maintains a nationwide registry of potential recipients
and provides organs and tissues to more than 15,000 recipients annually.
All organs are available without charge and shared based on need and a
first-come, first-served basis.
The modern history of organ transplantation is reviewed in this
article. The article is divided into solid organ transplantation (ie,
heart, lung, kidney liver), cell transplantation (ie, bone marrow, stem
cell, islet cell), and xenotransplantation. The history of tissue
transplantation is considered outside the scope of this article and is
not reviewed.
Early history of transplantation immunology
The predominant early theory regarding the mechanism of rejection was
malnutrition of grafted tissue as suggested by Paul Ehrlich in 1906.
Similarly, in 1910, Carrel noted that physiological disturbances in
transplanted organs were likely caused by biological factors. Soon
thereafter, Viennese pathologist Karl Landsteiner discovered the ABO
blood group system that eventually led to the introduction of clinical
blood transfusion. Sir Peter Medawar, who was awarded the Nobel Prize
for his pioneering work, defined for the first time the immunologic
nature of skin allograft rejection in humans. He confirmed that these
reactions are immunologic based on data from extensive animal
experimentation. In addition, George Snell observed that tumor grafts of
normal tissues were accepted between inbred animals but not between
animals of different strains.
As early as 1914, the fact that lymphocytes infiltrated grafts was
recognized; however, many years elapsed before an understanding of the
molecular basis of T-lymphocyte activation as a cause of acute rejection
was developed. Over the years, researchers recognized that the principal
targets of the immune response are the major histocompatability complex
(MHC) molecules on the graft. The T lymphocytes of the recipient
recognize the MHC by 2 different pathways. The direct pathway initiates
CD8+ cytotoxic T cells by interaction of human leukocyte
antigen (HLA); the indirect pathway activates CD4+ helper T
cells and leads to a delayed-type hypersensitivity response,
cell-mediated toxicity, and alloantibody production.
Advances in transplantation immunology
The genes responsible for immunologic reactions leading to graft
rejection were termed histocompatibility genes. Peter Gorer further
established that the major histocompatibility locus was antigene II, and
thus named the locus histocompatibility II. Further work in the area of
immunohematology by Jean Dausset led to the knowledge that MHC genes are
the most important markers of an individual’s biological identity.
Dausset noted that MHC genes are required for the presentation of
peptide antigens to T-cell receptors, and they play a vital role in
transplantation immunology. Ralph Zinkernagel and Peter Doherty added to
the growing pool of immunological knowledge and stated that the role of
the MHC is to "signal changes in self to the immune system."
Research on humans led to the discovery that genetic control of the
HLA resides on chromosome 6 in a supergene region known as the MHC.
Class I MHC antigens include HLA-A, HLA-B, and HLA-C. Furthermore, the
class II MHC antigens important in transplantation are governed by
HLA-DR, HLA-DP, and HLA-DQ. These regions on chromosome 6
are tightly linked and constitute a haplotype.
Manipulating the immune system
Knowledge of immunology led to the first successful kidney
transplantation between identical twins, in 1954. The initial work in
this field began with the recognition that organ allografts may be
transplantable. Peter Medawar performed skin grafts for victims of burns
during World War II. However, the grafts only succeeded when performed
between identical twins.
At Peter Bent Brigham Hospital in Boston, the possibility of treating
end-stage renal disease by kidney grafting was under active
investigation. In 1952, David Hume made early attempts at allografting
the kidney from an unrelated donor and found that the kidney graft
functioned well for a short period. One of their grafts survived several
months, and Hume reasoned that chronic uremia likely suppressed the
immune function of the recipient.
Joseph E. Murray performed the first successful identical twin renal
transplantation at Peter Bent Brigham Hospital in Boston. In 1959, this
team performed the first successful fraternal twin transplantation.
Despite massive irradiation of the host prior to transplantation, these
attempts were largely unsuccessful. Nonetheless, their efforts set the
stage for the evaluation of rejection and mechanisms to avoid it.
Over the next 25-year period, discoveries in immunosuppression paved
the way for attempts at manipulating the recipient’s immune system.
These research efforts eventually led to the discovery of lymphocyte
function, the role of the thymus in the ontogeny of the immune system
(1961), the delineation of the human MHC (1963), the distinction of the
T- and B-lymphocyte subsets (1968), and the demonstration of the MHC-restricted
nature of the adaptive immune response (1974).
Early efforts at immunosuppression
Initial attempts at controlling rejection began with experiments
involving total body irradiation. The initial evidence came in 1958 from
Paris, France, where Mathe, a hematologist, treated 6 Yugoslavians who
were accidentally irradiated on a previous occasion. The bone marrow
homografts in these patients were successful, which led the way for
irradiation to be used in other organ transplantation. Unfortunately,
for renal transplantation, irradiation alone led to dismal outcomes,
with only 2 reported successes: a single case by Merrill in 1960 and
another by Hamburger in 1962.
Further efforts to avoid and control rejection of transplanted organs
led to the investigations of medications. Robert Schwartz and William
Dameshek showed that the drug 6-mercaptopurine could prevent rabbits
from producing antibodies to foreign proteins. In 1961, Joseph Murray
prescribed 6-mercaptopurine for the first time to a human kidney
transplant recipient. The patient unfortunately died from drug toxicity.
Roy Calne at the Peter Bent Brigham Hospital experimented with
6-mercaptopurine and its close relative azathioprine, after he had
disappointing experience with total body irradiation.
Azathioprine used alone was not very effective in human
transplantation. Careful studies undertaken by Thomas E. Starzl in the
early 1960s, while he was in Denver, demonstrated that a combination of
corticosteroids and azathioprine led to much better success. The work of
Thomas Starzl transformed clinical transplantation into a clinical
service and ushered in the proliferation of transplantation programs in
kidney transplantation worldwide. Cortisone had been discovered in 1936,
as an adrenal gland steroid with immunosuppressive properties.
Prednisone, a cortisone derivative, was used subsequently in cadaveric
kidney transplant recipients. In 1964, David Hume noted that prednisone
not only was useful in preventing graft failure in regular doses, but it
was useful for reversing renal allograft rejection in larger doses.
However, continued use of corticosteroids permanently alters normal
immune function and produces other very serious adverse effects.
Discovery of cyclosporine
In 1972, Swiss biochemist Jean-François Borel discovered cyclosporine
in natural fungal byproducts. Cyclosporine improved graft rejection in
animals by inhibiting T-lymphocyte activity. Roy Calne investigated the
effects of cyclosporin in dogs with renal allografts and pigs with
orthotopic heart grafts. His work proved that cyclosporine was a much
better immunosuppressive agent than corticosteroids, azathioprine, or a
combination of both. Calne also found that cyclosporine was nephrotoxic;
work by other investigators on devising safe protocols for cyclosporine
led to marked improvement not only in kidney transplantation, but also
in successful transplantation of the lungs, heart, heart and lungs,
pancreas, and liver.
In the late 1970s, cyclosporine increased the 1-year survival rate of
liver allografts from 18% to 68%. Although cyclosporine is generally
associated with significant adverse effects, administration of small
doses in a controlled protocol results in minimal adverse events.
Cocktail approach
The cocktail approach, which combines cyclosporine with steroids and
azathioprine, was found to be the most effective approach to
immunosuppression for organ transplantation patients over the next 10-15
years. More recently, this combination has been replaced by regimens
that include newer immunosuppressive agents. Tacrolimus has almost
completely replaced cyclosporine in liver and pancreas transplantation,
and it is used in 50% or more of kidney recipients around the world.
Mycophenolate mofetil has largely replaced azathioprine in most organ
transplantation procedures. Additional new immunosuppressive agents that
have been approved include sirolimus, daclizumab, basiliximab, and
antithymocyte globulin (Thymoglobulin). Furthermore, a number of new
regimens are being explored that attempt steroid withdrawal or
avoidance, or calcineurin inhibitor withdrawal or avoidance.
Early
experimentation
In 1905, Carrel and Guthrie performed the first cardiac
transplantation in animals at the University of Chicago. This was a
heterotopic experimental transplantation. Parts of a small dog were
transplanted into the neck of a larger dog by anastomosing the cut ends
of the jugular vein and carotid artery to the aorta, the pulmonary
artery, one of the vena cavae, and the pulmonary vein. In 1933, Mann
transplanted a canine heart into the carotid-jugular circulation with
establishment of coronary perfusion. The longest survival was 8 days,
and he observed evidence of allograft rejection as the heart was
infiltrated with lymphocytes, mononuclear cells, and polymorphonuclear
cells. The work of Marcus and colleagues at Chicago Medical School
contributed to donor graft preservation and improved coronary perfusion
techniques.
Pioneering work by Demikhov
Vladimir Demikhov’s research greatly advanced the field of
experimental cardiac transplantation. His published works documented
many experiments, including transplantation of the head, transplantation
of halves of the body, and surgical combination of 2 animals with the
creation of single circulation. His initial work in cardiac
transplantation involved canine heterotopic cardiac transplants to the
inguinal region. His monograph reported a long series of 250
experimental efforts at transplanting a heterotopic intrathoracic
cardiac graft.
On June 30, 1946, Demikhov transplanted a heterotopic heart and lung;
the animal survived for 9 hours and 26 minutes. A subsequent experiment
on a dog resulted in 25 days of survival, and the cause of death was
probably dehiscence of the tracheobronchial suture line.
Graft preservation
Experiments in orthotopic transplantation began with Demikhov, who
attempted to maintain donor and recipient perfusion during anastomosis.
Problems associated with maintaining the recipient during transfer and
preserving the graft were addressed by Neptune and colleagues. Neptune’s
team transplanted the entire heart-lung block and maintained both the
donor and recipient in a cooler to maintain hypothermia. Webb and Howard
demonstrated that canine hearts that were heparinized and flushed in
potassium citrate could survive prolonged periods at low temperature.
When transplanted heterotopically, the function of these organs
returned. Webb and Howard also performed successful orthotopic
heart-lung transplantations in which the recipient was maintained with
cardiopulmonary bypass during transfer.
Advances in surgical techniques
In 1958, Goldberg and colleagues at the University of Maryland
performed orthotopic cardiac transplantations using an innovative
technique in which the left auricle was anastomosed with the left
atrium. This circumvented the problems associated with anastomoses of
individual pulmonary veins. This technique was further refined by Cass
and Brock, who used right and left atrial cuffs.
In 1960, Richard Lower and Norman Shumway described the modern
surgical technique of orthotopic cardiac transplantation. The recipient
was kept alive on cardiopulmonary bypass; the donor heart was immersed
in cold saline; and anastomoses were performed to the atria, pulmonary
artery, and aorta. The dogs that underwent transplantation survived and
resumed their regular activity; this generated an immense interest in
cardiac transplantation and further experimental work by other
investigators, including D.A. Blumenstock, who in 1963 reported that 50
of his dogs survived for periods ranging from 1-42 days. Deaths in these
dogs occurred secondary to acute rejection. Subsequent investigators
used immunosuppression and improved long-term survival; the
immunosuppressive drugs used included steroids, cyclosporine, and
azathioprine.
Human heart transplantation
By the mid 1960s, surgical techniques, methods of recipient support,
and methods of myocardial protection had been described. In addition,
transplant allograft rejection had been reported, and methods of
diagnosing and treating rejection were available. Legal and logistic
issues were the next hurdles that prevented heart transplantation in
humans. On December 3, 1967, the first successful human cardiac
transplantation was performed by Christiaan Barnard at Groote Schuur
Hospital in Cape Town, South Africa. The transplant recipient was a
54-year-old man with end-stage ischemic heart disease; the donor was a
young man with a severe brain injury. The recipient initially recovered
but subsequently died of Pseudomonas pneumonia 18 days later.
In 1967, Barnard described the operation: "The achievement did not
come as a surprise to the medical world. Steady progress towards this
goal has been made by immunologists, biochemists, surgeons, and
specialists in other branches of medical science all over the world
during the past decade to ensure that this, the ultimate in cardiac
surgery, would be a success."
On December 6, 1967, Adrian Kantrowitz performed a transplantation
from an anencephalic infant to an 18-month-old child using deep
hypothermia and circulatory arrest. Although the surgery went well,
postoperatively, the recipient developed metabolic and respiratory
acidosis, leading to cardiac arrest, and survived only 6.5 hours. The
autopsy showed diffuse atelectasis of both lungs.
After multiple attempts at cardiac transplantation in the late 1960s,
poor outcomes were achieved and interest in this procedure waned.
However, during the 1970s, an organized approach to cardiac
transplantation (mostly by the group at Stanford University) improved
the 1-year survival rate from 22% in 1968 to 65% in 1978. This success
occurred because of improved management of infectious complications,
better donor and recipient selection, and improved capabilities of
diagnosing and aggressively treating rejection. The widespread adoption
of cyclosporine use in the 1980s resulted in increased worldwide
enthusiasm for cardiac transplantation and much-improved long-term
survival.
Human heart-lung transplantation
Denton Cooley performed the first clinical heart-lung transplantation
on September 15, 1968. The team replaced the heart and lungs of a
2-month-old infant who had an atrioventricular canal defect with the
heart and lungs of an anencephalic infant donor; the recipient survived
only 14 hours, succumbing to respiratory failure. In 1982, Bruce A.
Reitz published the first successful clinical series of heart-lung
transplantations; the use of cyclosporine and the Stanford University's
group experience with experimental cardiopulmonary transplantation were
important contributing factors.