J Appl Physiol
89: 1681–1689, 2000.
historical perspectives
Transplantation and its biology:
from fantasy to routine
NICHOLAS L. TILNEY
Department of Surgery, Brigham and Women’s Hospital,
Harvard Medical School, Boston, Massachusetts 02115
allograft; rejection; lymphocyte; immunosuppression
ADVANCES IN MEDICINE AND RELATED sciences have long
complemented each other. A novel medical approach
may open new concepts in biology. Experimental data
produced years before may suddenly become relevant
in solving clinical conundrums. Organ transplantation
and its biology are examples of this parallel relationship. Each stemmed from relatively separate origins,
and each has increasingly cross-fertilized the other.
The startlingly successful resurrection of a patient
with end-stage renal failure by a kidney transplanted
from an identical twin in the 1950s brought to the
attention of professionals and the public that such a
radical departure in treatment of a hitherto fatal condition could have far-reaching future possibilities. In
contrast, the inevitable acute destruction of foreign
tissue grafted to normal subjects, initially an experimental curiosity, was later defined more precisely in
Address for reprint requests and other correspondence: N. L.
Tilney, Brigham & Women’s Hospital, 75 Francis St., Boston, MA
02115.
http://www.jap.org
controlled animal models and then in patients. A morphologically unprepossessing circulating cell, the lymphocyte, was recognized in the early 1960s to be immunologically competent and primarily responsible for
the rejection phenomenon. Over the ensuing years, the
cellular and molecular cascade involved in host alloresponsiveness (see Table 1) and graft destruction has
gradually been unraveled. Strategies to inhibit these
events were subsequently designed to allow successful
allograft placement into a recipient. These strategies
included total body x-radiation and then the use of
increasing numbers of chemical agents. More recently,
new generations of ever more effective immunosuppressive drugs have been developed; the actions of
these drugs have also been better understood on a
molecular level. In addition, as the associated physiological, immunologic, molecular, and pharmacological
puzzles presented by the subject have become progressively understood, the number of biological therapies to
produce specific unresponsiveness toward a foreign
graft has increased.
Significant developments in the evolution of transplantation and transplantation immunobiology will be
reviewed in this paper. The birth of the idea in fantasy
will be discussed first, and then early experimental and
clinical attempts, which ultimately have led to routine
clinical practice, will be reviewed. Although hardly
inclusive, a broad picture of this biomedical adventure
will be presented.
FANTASY
The transformation of a part of one individual into
another has been a theme recurring throughout lore
and literature since ancient times. The Egyptians and
Phoenicians worshipped gods bearing the heads of animals. In Greek mythology, creatures with attributes of
both humans and beasts were plentiful: Pegasus, the
fierce Minotaur, lusty Satyrs chasing nymphs through
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1681
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Tilney, Nicholas L. Transplantation and its biology: from
fantasy to routine. J Appl Physiol 89: 1681–1689, 2000.—The
replacement of diseased organs and tissues by the healthy
ones of others has been a unique milestone in modern medicine. For centuries, transplantation remained a theme of
fantasy in literature and the arts. Within the past five decades, however, it has developed from a few isolated attempts
to salvage occasional individuals with end-stage organ failure to a routine treatment for many patients. In parallel with
the progressive improvements in clinical results has come an
explosion in immunology, transplantation biology, immunogenetics, cell and molecular biology, pharmacology, and other
relevant biosciences, with knowledge burgeoning at a rate
not dreamed of by the original pioneers. Indeed, there have
been few other instances in modern medicine in which so
many scientific disciplines have contributed in concert toward understanding and treating such a complex clinical
problem as the failure of vital organs. The field has been a
dramatic example of evolution from an imagined process to
an accepted form of therapy.
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TRANSPLANTATION AND ITS BIOLOGY: A HISTORY
Table 1. Glossary of terms
Adoptive transfer
Allograft
Alloresponsiveness
Autograft
B lymphocyte
Bursa
Histocompatibility antigen
Hybridoma
IgG
IgM
Isograft
T lymphocyte
Tolerance
Xenograft
Transfer of activated cells (lymphocytes) into a naive isologous host
Graft from a member of the same species
Host immune reactivity to allografted tissue
Graft from the same subject
Bursa (equivalent) derived lymphocyte involved with antibody formation
An aggregation of lymphoid tissue near the cloaca of birds responsible for antibody production.
The bursa equivalent in mammals probably lies in the lymphoid tissue of the gut and in the
bone marrow
Antigens expressed on graft cell surfaces that are targets of host alloimmunity
B lymphocyte fused with a myeloma cell to produce an immortal line of cells that produce a
specific antibody
Immunoglobin G, an antibody with high affinity dependant on T cell help
Immunoglobulin M, an antibody with low affinity independent of T cell help
Graft placed between identical twins
Thymus derived lymphocyte responsible for cellular immunity
A state of specific unresponsiveness against a given antigen by a host in whom the remainder
of its immunologic repertoire is intact
Graft from a member of a different species
healthy leg of an Ethiopian by the patron saints of
transplantation, Cosmos and Damian. In these and
other examples, the richness of human fantasy has
long envisioned, at least theoretically, the goal of reconstructing or replacing diseased or missing parts
with healthy living tissue from others.
EARLY VENTURES
The concept of tissue transplantation was not totally
relegated to the imagination, as a few early physicians
devised practical methods to cover bodily defects that
are still used in modern reconstructive procedures.
Susruta, a surgeon of ancient India (⬃1000 BC), discussed in his monumental treatise, Susruta Samhita, a
technique for creating a new nose for those lacking one.
Nasal amputation, a popular form of punishment at
that time, forced many unfortunates into lives of misery and disfigurement. Susruta devised a skin flap
from cheek or forehead to cover such large defects. This
idea was embellished further by Gasparo Tagliacozzi in
16th century Bologna, a period when swordplay was
rife, punishment mutilative, and syphilis, with its destruction of nasal cartilage, endemic in Europe following the discovery of the New World. Tagliacozzi formed
a pedicle flap from the upper arm to restore such
defects. Once healed in place, the other end of the
pedicle was released from the arm and fashioned into
an appropriate shape. Later, in an article in the Gentleman’s Magazine of October 1794, a description of the
continuing practice of rhinoplasty in India produced
much excitement in England for two reasons: the interest in Indian affairs during the expansion of the
Empire, engendered by such political figures as Robert
Clive, Warren Hastings, and William Pitt, and the
influence of the experimental surgeon John Hunter.
Hunter’s observation that the spur of a rooster would
grow normally when transferred from its foot to its
highly vascularized comb intrigued natural philosophers of the time (Fig. 1). He followed this experiment
with the successful replacement of the first premolar of
a patient several hours after it had been knocked from
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classical landscapes. Snakes coiled from Medusa’s
scalp; those who caught her glance turned to stone.
Homer sang of the sailors of Ulysses transmogrified
into swine by the enchantress, Circe. Indeed, his Chimera, part goat, part lion, and part dragon, has become
a modern symbol of clinical transplantation. Virgil
described his own utopian Arcadia, that peaceful landscape of the boy-god Pan and other beast-gods. The
tradition has also flourished in children’s fairy tales
and in adult literature, as exemplified by descriptions
of the inhabitants of Heaven and Hell by Dante, Milton, and later by Blake. The features of Stevenson’s Dr.
Jekyll were converted reversibly into those of Mr.
Hyde, and the face of Wilde’s Dorian Gray altered
drastically as his character deteriorated. On his island,
H. G. Wells’ Dr. Moreau created humanoid forms from
animals by sequential surgery.
The use of specific tissues for restoration or reconstruction was only occasionally considered. Although
pagans, infidels, and believers alike were adept at
removing skin for punishment, no record suggests that
this tissue was ever used for therapeutic purposes.
Mercury excised a sheet of skin from Marsyas, whereas
St. Bartholomew, as portrayed by Michelangelo, holds
his own skin, skillfully flayed by the Indians, which he
will be able to reclaim on Judgment Day. Early Christians reflected on the benefits of tissue replacement but
as a supernatural event. Christ, for instance, restored
the ear of a servant of the high priest following its
amputation by an angry Simon Peter. St. Peter, having
witnessed this accomplishment, was later able to replant the breasts of St. Agatha, which had been pulled
off with tongs during torture. St. Mark replaced a
soldier’s hand lost in battle. In the 5th century, Pope
Leo I, tempted by a woman kissing his hand, cut it off.
The hand, however, was restored by the Virgin Mary,
appearing in a vision, as a reward for resisting further
temptation. In the 12th century, St. Anthony of Padua
replanted the leg that a young boy had amputated in a
fit of remorse after kicking his mother. The best known
restoration with saintly surgery was the replacement
of the gangrenous leg of a bell tower custodian with a
TRANSPLANTATION AND ITS BIOLOGY: A HISTORY
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Fig. 1. A cock’s spur was successfully transplanted to
its comb by John Hunter in 1770 (from the Hunterian
Museum, Royal College of Surgeons of England).
burned children, both their own and that of their mothers. The healing of the patient’s own skin but not the
maternal grafts provoked him to conjecture about the
importance of genetic differences between individuals as
well as to note that the tempo and intensity of destruction
increased after a second grafting from the initial donor
but not from a third party. On three occasions during the
next decade, surgeons in Germany and the United States
successfully treated deformities and burns with
isografted skin from identical twins. These occasional
clinical observations were placed on a more scientific
basis during World War II, however, by a young Oxford
zoologist, Peter Medawar (Fig. 2), working with Thomas
Gibson, a plastic surgeon in Glasgow. Pairing autografts
and allografts on patients, they concluded that the latter
were inevitably destroyed but also observed, as had Holman, that destruction of second grafts from the same
foreign donor was hastened. “The second set of . . . grafts
did not undergo the same cycle of growth and regression
as the first; dissolution was far advanced . . . after transplantation.” Here, we find the first use of the term “second set,” a definition that was to be widely used to
describe the phenomenon of “memory” in allografting.
Equally as important, however, was their final conclusion
that such accelerated rejection “was brought about by a
mechanism of active immunization.” Medawar carried
forward his investigations in rabbit models and began to
determine in detail the meaning of morphological
changes associated with the phenomenon of rejection of
foreign tissue grafted to a genetically dissimilar host. His
findings would later become the basis for increased interest in transplantation biology, which soon led to an explosion of activity into the meaning of the immune system and the function of cells and tissues that comprise it.
JINGOISM OF THE BODY: THE IMMUNE RESPONSES
With both the stirrings of clinical activity in kidney
transplantation after World War II and data becoming
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his jaw and then engrafted a human tooth into a cock’s
comb. Resultant clinical efforts in transplantation of
teeth, however, a short-lived misadventure of the latter
18th century, not only exploited the poor as donors but
often ended in infection and death of the recipients.
From these beginnings and persisting until after
World War II, sporadic reports of the transplantation
of skin and other tissues occasionally caught the interest of surgeons. In 1804, shortly after Hunter’s death,
the Milanese surgeon Guiseppe Baronio published an
account of the grafting of skin between a variety of
animal species, noting in passing that those from the
same animal healed and those from others did not.
These studies encouraged the transfer of skin grafts
from one part of a patient to cover a raw surface on
another site too large to be closed primarily or with a
flap. In 1817, Astley Cooper, a surgeon at Guy’s Hospital, amputated a thumb and used the remaining skin
as a graft to cover the stump. By the end of the 19th
century, skin autografts were used relatively frequently to treat many open ulcers and nonhealing
wounds. A more exotic form of transplantation arose,
during and after World War I, when the grafting of
testes from monkeys, goats, and other animals was
used to rejuvenate the weary and increase the sexual
appetites of older men. Initiated in 1916 by Chicago
surgeons, popularized in the 1920s in Paris by Serge
Voronoff, and continued through the 1930s in Switzerland and in Kansas, the reputed efficacy of glandular
grafting gained much public attention. With its overlay
of charlatanism, however, the practice declined and
eventually ended, although at the time it appeared to
be a natural extension of the use of newly discovered
extracts of endocrine glands.
However, despite hints from several investigators,
there was little general appreciation of differences in
behavior between autografts, allografts, and xenografts
(see Table 1). In the 1920s, Emile Holman, a young
surgeon working in Boston, grafted skin on several
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TRANSPLANTATION AND ITS BIOLOGY: A HISTORY
available from a few experimental models, the dramatic and complex series of host immunologic responses called into play by and leading to the destruction of foreign tissues provoked increasing interest
among scientists. Indeed, the concept that such activity was on an immune basis and was moderated predominantly by lymphocytes took a long time to develop.
The basic features of inflammation (heat, redness,
swelling, and tenderness) have been recognized since
the writings of Celsus and Galen. Details of the process, however, remained unclear until 1872 when the
German pathologist Julius Cohnheim described the
migration of leukocytes from blood vessels into the
injured or inflamed footwebs, mesentery, and tongues
of frogs. In 1905, Elie Metchnikoff, a Russian zoologist
working in Paris, demonstrated the central importance
of cellular activity in inflammation, first examining the
reactions of simple organisms to foreign bodies and
then expanding his observations up the evolutionary
scale to the vertebrates. Controversy raged during this
period regarding whether cellular activity or serumbased humoral factors, generally considered the most
important, were responsible for innate or acquired
immunity to infection. The polemics became so strident
that they drew public ridicule, fueled particularly by
George Bernard Shaw in the Doctors Dilemma. However, calm was restored when the 1908 Nobel Prize for
Physiology and Medicine was awarded jointly to
Metchnikoff for his observations on cell-mediated
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Fig. 2. Peter Medawar opened up the field of transplantation
biology with his experiments on acute rejection and immunologic
tolerance.
events and to Paul Erlich, the principal supporter of
the humoral theory, which was based on his “side
chain” hypothesis. It had also become clear at that time
that recovery from infection was often accompanied by
“immunity” or resistance to a subsequent exposure
from the same organism, a critical observation based
on the 18th century smallpox vaccination experiences
of Cotton Mather and Zabdiel Boylston in Massachusetts and Edward Jenner in England.
The often heated controversy between Metchnikoff,
Ehrlich, and others on the importance of cells and
antibodies in the host defenses was rekindled after
World War II because of increased interest in allograft
rejection. Medawar had become the highly visible proponent of cellular immunity, and Peter Gorer advocated the role of humoral antibodies in this dramatic
process. Although the dialogue was conducted on a
more genteel level than that which occurred a halfcentury previously, it engaged much attention among
those in the field. After completion of his medical studies at Guy’s Hospital in London, Gorer joined the great,
albeit difficult and eccentric, geneticist J. B. S. Haldane. His important research in the 1930s led to the
discovery of H-2 in the mouse, the first major histocompatibility (MHC) locus to be identified. His subsequent
observations, complementing experiments by George
Snell at Bar Harbor, Maine, whom Gorer spent a year
with, produced the general concept of “histocompatibility genes,” transplantation antigens that were to become a mainstay of research in the field and that
opened up the new area of tissue typing between donor
and recipient. By crossbreeding and backcrossing generations of inbred strains of mice, Snell, who won the
Nobel Prize in 1980, was able to segregate several
histocompatibility systems, later identified as genes.
Gorer then noted that the mice could only make antibodies against foreign H-2, a finding that made him a
major proponent of their role both in transplantation of
tissue and in the behavior of a host toward tumor
antigens. In modern immunology, the concept of the
MHC and its related components has become a critical
piece of the puzzle of activation and interaction of T
cells with foreign antigens, triggering intense and ongoing investigations in defining the role of the phenomenon in initiating the rejection event and stimulating
strategies to modulate it.
Medawar’s descriptions of “the homograft (allograft)
response” involved the sequential changes occurring in
rejecting skin grafts and in their draining lymph
nodes. Indeed, it was becoming clear that the lymphoid
system, developing relatively early in evolution and
attaining remarkable functional sophistication in
higher animals, was important in immune responses.
For instance, no lymphoid organs are recognizable in
most subvertebrates, which can mount only sluggish,
nonspecific inflammation against foreign stimuli. In
contrast, less primitive organisms such as annelid
worms and tunicates can reject foreign grafts slowly
via activity of their predominant blood cell, the hemocyte, which can evoke a weak inflammatory response,
has phagocytic properties, and can elaborate bacterio-
TRANSPLANTATION AND ITS BIOLOGY: A HISTORY
role in immunity. They were to receive the Nobel Prize
for this work.
The burgeoning information about cellular and humoral function as mediated by the mammalian thymus
and the avian bursa or mammalian bursa equivalent,
respectively, stimulated a torrent of immunologic studies relating to the activities of lymphocytes, which
continue unabated to the present time. These included
the gradual understanding that there were different
subpopulations with differing functional behavior. In
1966, Henry Claman and his colleagues from Colorado
published observations that effector lymphocytes
needed the influence of another lymphocyte population
before they could produce antibody. A few years later,
Avrion Mitchison and his group in London defined
more precisely the “help” given by thymus (T)-derived
lymphocytes to bone marrow [bursa (B)]-derived lymphocytes in antibody production. The subsequent identification of specific T and B cell markers unequivocally
confirmed the presence of these two distinct subpopulations. Identification of histocompatibility antigens
and elaboration of their critical role at both cellular
and molecular levels have continued to unfold. The
rapid advances in hybridoma technology allowed the
creation of monoclonal antibodies in the 1980s. Such
antibodies, designed against specific antigenic determinants on cell surfaces, have facilitated characterization of the cellular cascade mediating allograft rejection and allowed progressive understanding of the
activities, interrelationships, influences, and contributions of cell populations, subpopulations, and their
factors in the host defenses. The recent explosion in
molecular biology and the elaboration of T cell receptors and their interaction with the T cell-MHC complex
have allowed the further unraveling of the complexities of host immunoresponsiveness. Entire fields concerning the function of various cell products such as
cytokines, accessory molecules, and adhesion molecules have burgeoned. In addition, it must be stressed
that, only 35 years ago, particulars about the lymphocyte, its function, and its properties were not understood.
REALITY: THE KIDNEY
Emboldened by advances in anesthesia, antisepsis,
and surgical methods, a few investigators during the
opening years of the 20th century began to explore the
possibilities of renal transplantation in animals and
occasionally in humans. In 1902 in Vienna, Emerich
Ullmann reported the transfer of kidneys from their
location in the flank to the necks of dogs and goats
using prosthetic tubes and rings to join the vessels.
During the same period in Lyon, having developed and
refined direct suture techniques for vascular anastomosis, Alexis Carrel began to transplant kidneys into
experimental animals. As his experience grew, first
with Charles Guthrie in Chicago, then at the Rockefeller Institute, he began to realize that grafts from
the same animal survived and functioned, whereas
those from other animals inevitably failed, explaining
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cidal substances. The lowest marine vertebrates, hagfish and lamprey, have erythrogenic splenic tissue in
the submucosa of the gut as well as crude circulating
granulocytes. They can also produce IgM antibodies.
The cartilaginous and bony fish have a well-developed
spleen and thymus gland and can mount a cellular
response that causes rejection of skin grafts and form
both IgM and IgG. Birds are the first to elaborate
distinct classes of specific humoral antibodies via specialized lymphoid cells in the bursa of Fabricius, a
cloacal outpouching. Cellular immunity, mediated via
lymphocytes schooled in the thymus, and antibodymediated humoral activity from bursa-associated lymphocytes in the gut and bone marrow have reached
their most sophisticated and complex forms in mammals. Taken in bulk, mammalian lymphoid tissues
constitute an organ of considerable size, the overall
function of which, surprisingly, is still not completely
defined. One theory was proffered by Australian immunologist McFarland Burnet, who shared the Nobel
Prize in Medicine with Medawar in 1960. He conceptualized that these tissues and their associated lymphocytes are involved in “immunologic surveillance,”
the identification and elimination of genetic errors
occurring occasionally in rapidly dividing cells that
may become neoplastic. Even more importantly, it was
realized that, although populations of leukocytes destroy opportunistic microorganisms that may threaten
the subject throughout its life, resident lymphocytes
orchestrate continuing host immunity against further
challenge. An understanding of their role in transplantation came later.
After Medawar showed that host lymphocytes gathering in the bed of skin allografts preceded complete
tissue destruction, the increasing attention afforded
these cells during the 1950s and 1960s represented a
dramatic change in attitude from a few years before. In
the 1930s, Arnold Rich, a pathologist at Johns Hopkins, summarized existing knowledge about lymphocytes by concluding that they were merely “phlegmatic
spectators watching the turbulent activity of phagocytes.” Despite the fact that their function could only be
conjectured through static morphological studies, clues
were already present to indicate their importance in
the body’s defenses. The presence of small lymphocytes
surrounding tubercles or luetic lesions and in patients
with certain types of chronic inflammation had been
repeatedly described. They were also noted to congregate in the vicinity of particular types of tumors and
allografts. Their ability to initiate an immune response
by interaction with antigen was first appreciated in
graft-vs.-host models in the early 1950s. In the 1960s,
James Gowans in Oxford demonstrated that a large
proportion of such cells continuously recirculate
through tissues, lymph, and blood and confirmed that
they were “immunologically competent” by their ability
to reject stable skin grafts after adoptive transfer.
About the same time, Rodney Porter in Oxford and
Gerald Edelman in New York defined immunoglobulin
structure, opening the way for increased understanding of antibodies produced by lymphocytes and their
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TRANSPLANTATION AND ITS BIOLOGY: A HISTORY
Fig. 3. David Hume, one of the pioneers of clinical kidney transplantation.
because of interruption of lymphatics, denervation,
changes in temperature during placement, sepsis, or
breakdown of the ureteral anastomosis, the results of
the ongoing experiments with allografts in dogs by
surgeon Joseph Murray (Fig. 4) were more optimistic.
It had also become recognized that isologous skin
placed between identical twins survived indefinitely;
therefore, the Brigham group elected to transplant the
patient with a kidney from his twin. Placed in a retroperitoneal position behind the abdominal wall by Murray, the graft functioned immediately, reversed the
patient’s uremia completely, and sustained him normally until he died 9 years later of a myocardial infarction. As the clinical experience with similar cases increased over the next few years, lingering physiological
questions were answered, including the influence of
short periods of ischemia on immediate graft function
and whether denervated kidneys and ureters could
behave normally. It became obvious that individuals
with end-stage disease could be rehabilitated totally by
a successful transplant. Several female recipients of
kidney isografts became pregnant and delivered normal babies. Children whose growth had been stunted
by renal failure grew rapidly after restoration of function. The reversal of anemia in some individuals suggested that the transplanted organ could elaborate
erythropoietin. At least in the context of identical
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this difference on the basis of some undefined host
activity. Guthrie became discouraged by the inevitably
of this event despite technical perfection in organ
placement and left this field for other avenues of research.
The earliest kidney transplants were attempted in
humans as desperate measures to salvage individuals
dying of renal failure. Carrel’s teacher in Lyon,
Mathieu Jaboulay, performed the first two recorded
human kidney transplants in 1906 by suturing the
donor organ to the recipient arm vessels. In 1909,
Ernst Unger in Berlin engrafted both kidneys of a
Macaque monkey to the femoral vessels of a 21-yearold seamstress, a procedure stimulated by the new
knowledge that monkeys and humans were serologically similar for red cell antigens. In the 1930s, the
Russian surgeon U. U. Voronoy performed kidney
transplants in six patients poisoned by chloride of
mercury. None functioned. He also may have been the
first to detect specific serum antibodies in graft recipients.
After the end of World War II, a few surgical investigators once again became interested in the subject,
comparing the deteriorating function of the rejected
renal allografts with changes in their morphology and
with immunologic events occurring in the canine host,
much based on Medawar’s previous observations of the
rejection of skin grafts in rabbits and mice. In 1947 at
the Peter Bent Brigham Hospital in Boston, Ernest
Landsteiner, Charles Hufnagel, and David Hume (Fig.
3) anastomosed the vessels of a kidney taken from a
cadaver to the antecubital vessels of a young woman
with acute renal failure. The graft diuresed transiently
as she recovered her native function. In 1950, Richard
Lawler in Chicago engrafted a cadaver donor kidney to
the patient’s own renal vessels, directly joining allograft and recipient ureters. This organ appeared to
work long enough to allow the remaining native kidney
to recover and sustain the patient for 5 years. Beginning in 1951, Marcel Servelle, Charles Dubost, Rene
Küss, and their colleagues in Paris placed renal allografts in eight immunologically unmodified hosts, none
of which functioned for significant periods. About the
same time, Hume initiated a series of cadaver kidneys
in nine recipients. The surprising 5.5-mo survival of
the last of these patients was explained by the immunosuppressive effects of uremia as well as by unidentified similarities between donor and host. As dialysis
slowly became a reality during this period, interest in
treatment of those with end-stage renal disease was
building. In practical terms, however, enthusiasm was
muted by the universal failure of the transplants. Küss
summarized the state of the new subject in the early
1950s: “The results from medical teams in France as
well as the United States led us to believe that transplant surgery was impossible.”
It was with this background that one of a set of
identical twins who had developed renal failure arrived
late in 1954 at the Brigham Hospital. Although older
experimental studies had suggested that initially wellfunctioning autotransplanted kidneys ultimately failed
TRANSPLANTATION AND ITS BIOLOGY: A HISTORY
twins, transplantation of the kidney was a remarkable
success.
BREAKING THE IMMUNOLOGIC BARRIER
As ever-increasing numbers of patients dying of renal disease presented themselves for help and as even
more were being sustained by the equally new modality of hemodialysis, it became obvious that the immune
responses had to be modified for the successful engraftment of kidneys from genetically dissimilar sources.
The experimental work of Medawar and his colleagues
on the creation of neonatal tolerance to specific skin
allografts by early exposure of mice to the donor antigens suggested that such a concept was possible. The
problem was how to produce such a state clinically. The
only method of immunosuppression then available was
x-radiation with and without the coincident administration of allogeneic bone marrow, which had been
shown to prolong skin graft survival in mice and other
species. By the late 1950s, a series of patients in Boston
and Paris underwent sublethal radiation before receiving a cadaver kidney. Although all except two died
quickly of systemic infections, the courses of those two
survivors were unprecedented: a patient from Boston
lived normally for 20 years supported by his transplant
and without additional immunosuppression; the other,
from Paris, lived for 26 years. Both died of causes
unrelated to their renal disease.
In 1959, Robert Schwartz and Walter Dameshek of
Tufts University in Boston reported that an anti-metabolite, 6-mercaptopurine (6-MP), could inhibit antibody formation in rabbits, the first inkling that a drug
could effect the immune responses. Roy Calne, an English surgeon, and Charles Zukoski at the University of
Virginia reported independently that kidney graft survival could be increased in dogs treated with this
agent. Azathioprine, the imidazole derivative of 6-MP,
was then shown by Calne and Murray to prolong substantially the survival of kidney transplants in dogs
and later in humans. The synergistic combination of
azathioprine plus adjunctive corticosteroids remained
the linchpin of immunosuppression for the next two
decades. Murray was to receive the Nobel Prize in
Medicine in 1990 for opening up the field with his early
work.
A variety of secondary immunosuppressive modalities were tested, and refinements in patient care were
instituted during the next two decades; during this
time, anti-lymphocyte serum and its derivatives were
introduced. Although the results of this class of agents
were inconclusive, they presaged the later use of the
more effective anti-T cell monoclonal antibody, OKT3,
used to treat acute rejection episodes in human allograft recipients. The influence of tissue typing, the
prognostic significance of presensitization of the recipient by serum antibodies directed against a potential
donor, and the effects of organ perfusion and storage on
graft survival all became separate fields of study. The
concept of brain death emerged as a means to use
organs from heart-beating cadavers for transplantation. Other substantive clinical improvements involved
both a marked decline in recipient mortality and a
modest increase in short-term graft success. Understanding of the pathophysiology of renal failure and its
dialytic control, better perioperative techniques, and
appreciation of the limitations, side effects, and toxicities of the available chemical and biological immunosuppressive agents all contributed to the gradually
improving results.
However, even with the advances during this period
of retrenchment and consolidation and despite accelerating related scientific knowledge, patient mortality
remained high and graft survival was unsatisfactory.
In 1977, for instance, data from over 9,000 recipients of
renal transplants throughout North America were analyzed and reported. At 1 year, the survival of recipients of most living-related donor kidneys was 90%;
however, the survival rate was only 75% for recipients
of cadaver grafts. The rate of graft function at 1 year
was even more dismal, with 70% of nonidentical livingrelated donor kidneys continuing to sustain their recipients but only 45% of cadaver donor grafts. By 5
years, these rates had dropped to 60 and 30%, respectively, a rate of attrition primarily due to chronic rejection and recipient death. Indeed, continuous maintenance immunosuppression not only caused many
patients to die of opportunistic infections, primarily
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Fig. 4. Joseph Murray performed the first successful renal transplant between identical twins and was the first to use chemical
immunosuppression in patients receiving allografts. He received the
Nobel Prize in 1990 for this work.
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TRANSPLANTATION AND ITS BIOLOGY: A HISTORY
fungi and viruses, but also produced a surprisingly high
incidence of cancer. The side effects of chronic steroids
were also difficult for many individuals to bear, particularly facial changes, obesity, easily damaged skin, and a
high incidence of osteonecrosis and fractures.
CYCLOSPORIN A AND BEYOND
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Despite these mediocre results, clinical transplantation continued to expand substantially during the
1970s with ever-increasing numbers of kidneys grafted
in ever-growing numbers of centers in many developed
countries. The subject was becoming progressively recognized as a treatment option both among physicians
and among the swelling roster of patients with endstage renal disease seeking help. However, the relatively disheartening plateau in results was to end
abruptly. In a November 1979 issue of Lancet, Calne
and his colleagues at the University of Cambridge
published the unprecedented courses of 34 recipients of
36 organ allografts, all treated with a new immunosuppressive drug, cyclosporin A. The majority of kidneys
(26 of 32) continued to support their hosts, as did two
pancreases and two livers. Twenty patients received no
coincident steroids; no additional immunosuppression
was used in 15.
The introduction of this agent, an extract from the
culture broth of a new strain of fungi imperfecti isolated by field botanists from the Sandoz (now Novartis)
Company in Switzerland, radically changed the complexion of clinical transplantation. Along with many
other compounds, this material was screened in the
laboratory of Hartmann Stähelin for pharmacological
activities other than the expected antimicrobial properties, particularly for any immunosuppressive effects.
By 1972, a young scientist, Jean Borel, had found that
one of the metabolites from the crude extract had
potent immunosuppressive effects in animals. Within
months, the influence of cyclosporin A on both cellular
and humoral immunity had been established in cultured cells, and its striking effectiveness in treating
experimental arthritis and in prolonging the survival
of skin grafts in mice was piquing general interest. The
material soon traveled to Calne’s laboratory where it
was quickly found to substantially prolong the survival
of organ transplants in several demanding animal
models. Investigators in other centers in Europe and
North America became involved. Interest grew quickly,
and clinical trials were initiated. By 1983, the results
of several multicenter trials had confirmed that a 20%
increase in 1-year kidney graft survival could be expected compared with conventional therapy and that a
10–15% improvement persisted at 3 and 5 years.
The effectiveness of this new modality also promoted
the rapid growth of transplantation of other organs
during the 1980s, particularly the liver, the heart, and
later the pancreas. Although there had been a few
laboratory and clinical attempts to graft these organs
in the 1960s, the results had been so unsatisfactory
that few of the enthusiasts persisted. However, the
introduction of cyclosporin resulted in an increased
success of such transplants toward that obtained with
kidney transplants, and their grafting has become virtually routine in the majority of centers throughout the
world. The introduction of a newer generation of immunosuppressive agents during the 1990s, each with a
unique activity on the immune responses, have also
begun to attract increasing interest. Several have become available for clinical use, including FK-506, mycophenolate mofitil, and rapamycin. Indeed, with these
new drugs alone or in combination, the incidence of
acute rejection has declined significantly and the overall success rates of most organ transplants are as high
as 85–90% by the end of the first year.
It appears that the next 50 years of transplantation
will depend less on chemical agents than on biological
strategies. Preclinical and clinical trials with cellular
transplantation, particularly of pancreatic islets and of
neural cells, are currently underway and are beginning
to include myocytes, vascular endothelial cells, and
other populations as well. The grafting of islets in
diabetics is beginning to provide promising results
after decades of failure. The use of monoclonal antibodies directed against particular cell classes and their
products continues to hold some promise, although
probably less than anticipated. Enlivened by the revolution in cellular and molecular biology during the past
decade, the means to produce permanent host acceptance of allografted organs are increasingly under
study. The state of specific tolerance or unresponsiveness to a graft with the remainder of the host immunologic repertoire remaining intact has been described
as the “Holy Grail” of transplantation since the initial
report of neonatal tolerance by Medawar and colleagues in 1953. Although the success of this concept,
particularly in large animal models or in humans, has
been relatively unconvincing, newer insights appear to
be making its induction more of a reality. Accruing
experimental knowledge about the importance of various accessory molecules in the interaction between T
lymphocytes and graft antigens and the means to produce specific host unresponsiveness by inhibiting their
activity, for instance, is garnering much interest. The
production of tolerance would be of aid in xenotransplantation, a subject that is becoming increasingly
important as the divergence between donor supply and
patient demand becomes ever greater. Despite much
effort toward modulation of the fulminate initial rejection process triggered by cross-species transplantation,
however, substantial advances have come slowly. An
alternate approach of potential but as yet unfulfilled
promise is to alter genetically donor animals, primarily
pigs, so that their organs may more closely resemble
those of humans and be less prone to host immune
responsiveness. The recent success in cloning large
animals also opens a variety of possibilities in this
regard. Finally, chronic rejection remains the most
important reason for long-term graft loss, despite effective control of acute rejection. The influence of initial nonspecific graft injury may be increasingly important in the evolution of this process. Antigenindependent, donor-associated conditions such as brain
TRANSPLANTATION AND ITS BIOLOGY: A HISTORY
death and ischemia-reperfusion injury have been especially implicated. Efforts are underway to modulate the
initial inflammation resulting from the early insults and
to match more effectively the demographics of donors and
recipients so that less than optimal organs from “marginal” or “extended” donors can be normalized to resemble
more optimal ones from living sources. Thus it appears
that, in the next phase of clinical transplantation, a
variety of biological means to produce host unresponsiveness will be used, alone or in combination with chemical
immunosuppression, that will allow prolonged survival
and function of foreign organs and tissues that have
replaced the failed ones of patients.
SELECTED READINGS
1. Hamilton DNH. The Monkey Gland Affair. London: Chatto and
Windus, 1986.
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2. Hamilton DNH. Kidney transplantation: history. In: Kidney
Transplantation: Principles and Practice (3rd ed.), edited by Morris PJ. Philadelphia, PA: Saunders, 1988, p. 1–14.
3. Hume DM, Merrill JP, Miller BF, and Thorn GW. Experiences with renal homotransplantation In the human: report of
nine cases. J Clin Invest 327–382, 1955.
4. Küss R and Bourget P. An Illustrated History of Organ
Transplantation. Rueill-Malmaison, France: Laboratories Sandoz, 1992.
5. Medawar PB. Memoir of a Thinking Radish. Oxford: Oxford
Univ. Press, 1986.
6. Moore FD. Give and Take. Philadelphia, PA: Saunders, 1964.
7. Saunders JB de CM. A conceptual history of transplantation.
In: Transplantation, edited by Najarian JS and Simmons RL.
Philadelphia, PA: Lea & Febiger, 1972, p. 3–25.
8. Tesatti B. Transplantation and reimplantation in the arts. Surgery 75: 389–392, 1974.
9. Terasaki PI. (Ed.) History of Transplantation in Thirty-Five
Recollections. Los Angeles, CA: UCLA Tissue Typing Laboratory
Publications, 1991.
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