Краткая история клинической трансплантологии

Резюме

Трансплантация органов - одно из наиболее ощутимых и эффективных достижений XX в. На- чиная с первых технических неудач в начале века и небольшого количества научных предска- заний исследователей-провидцев в середине века клиническая трансплантология очень быстро стала не только практической дисциплиной, но и примером огромных возможностей прогресса медицинской науки. История трансплантологии изложена в ряде монографий, и хотя в на- стоящей статье мы не затрагиваем все аспекты исторических событий, было важно выделить основные моменты, обеспечившие сегодняшний уровень специальности: яркий пример силы объединения науки и медицины для общего блага. 

Ключевые слова:клиническая трансплантация, история

Клин. и эксперимент. хир. Журн. им. акад. Б.В. Петровского. 2017. № 3. С. 7-17.

Статья поступила в редакцию: 01.05.2017. Принята в печать: 15.06.2017. 

Данная статья, подготовленная специально для журнала "Клиническая и экспериментальная хирургия", является модифицированной рукописью из руководства Американского общества трансплантологов. Большая часть текста была опубликована в главе Сэра Роя Кална в Руководстве по трансплантации под редакцией доктора Аллана Кирка из Университета Дюка.

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Transplantation is one of the most visible and impactful medical accomplishments of the 20th century. Arising from technical advances and insights of the early 20th century, the concept that transplantation was technically feasible gave rise to earnest investigations into its physiological barriers by a small number of visionary investigators driven by recognized clinical problems. From their descriptions of the genetic and immunological basis for graft rejection and the pioneering work of the first transplant surgeons, the clinical practice of transplantation rapidly became interwoven into the fabric of clinical care, not only from a practical standpoint but also as an example of the immense possibilities and challenges inherent in advanced medical practice. Multiple concepts now taken for granted in modern medical practice, such as immunosuppression, monoclonal antibody use, and indeed the concept of death as a definable state, have their origins in transplantation. Numerous modern ethical quandaries also trace their roots to problems introduced by transplantation.

The history of transplantation has been the subject of numerous books, and while its in-depth treatment is not practical in this text, it is important to make evident the major contributions that brought the field to where it stands currently: a prime example of the power of science and medicine combined for a common good.

The Concept of Transplant Surgery

The idea of organ transplantation is a surgical concept based on an understanding of anatomy and the physiological requirements of an organ to stay viable and fulfil its biological role. Its origins relate to intuitive concepts of like replacing like that date back hundreds of years, including the oft cited Catholic miracle of Cosmos and Damian. However, its serious pursuit arose independently from work conducted in a number of European countries in the early 20th century, the products of which led to the kidney as the chief candidate for speculations on organ transplantation. Kidney failure was a relatively common fatal condition, the physiological role of the kidney was understood and the kidneys were well defined anatomically. Importantly, it was recognized that one well functioning organ was sufficient to maintain an individual in good health for a normal lifespan. The kidney’s essential anatomical connections, namely a single artery and vein and a urinary drainage vessel, were apparently sufficient for it to perform its physiological role. Nerves, lymphatic and fascial connections, although important, did not seem to be essential. At the beginning of the 20th century Alexis Carrel (Fig. 1) devised a method of joining blood vessels together surgically [1], a technique that became the subject of his 1912 Nobel Prize in Physiology or Medicine. Carrel himself used this technique to show that a kidney could be removed and transplanted and would function after restoration of the arterial in-flow and venous out-flow, provided these surgical procedures were undertaken expeditiously, since a prolonged period without a blood circulation led irreversible damage from ischaemia.

In cats and dogs Carrel and Guthrie proved the technical feasibility of the operation and also observed that moving a kidney from an animal to another site in the same animal could result in longterm survival of the kidney and the animal after removal of the opposite kidney [2]. However, transplanting a kidney from one individual to another, after a short period of satisfactory kidney function, was soon doomed to failure. Carrel recorded this observation, but at that time there was no explanation for the fairly rapid failure of what are now called renal allografts [3]. Priority for the transplantation of a kidney in a human patient has been claimed and disputed by a number of surgeons and their historians. Transplants to the brachial or femoral vessels of human kidneys or animal kidneys to humans were described. The early claims and a critical discussion of these unsuccessful experiments can be found in Francis Moore’s book “Transplant” 1964 ed. Saunders [4]. None of them functioned for a long period of time and with hindsight the procedures were premature in relation to the knowledge that was gradually accumulating from Carrel and Guthrie’s experiments.

Transplant Biology

In the 1940-1950s Simonsen and Dempster independently described experiments similar in nature to those of Carrel and Guthrie and long-term, life-sustaining function of autografts was confirmed. However, experimental allografts were shown to fail universally and a second kidney transplanted from the same donor to the same recipient was destroyed almost instantaneously. These observations were the culmination of many years of painstaking research by Morten Simonsen in Denmark and William Dempster in London who also reported on the use of cortisone in renal allograft recipients. Both workers described histological changes that occurred in renal allografts. The renal cortex became infiltrated with neutrophils, eosinophils, macrophages, lymphocytes and pyronin- positive plasma cells, and these inflammatory changes were accompanied by necrosis of nephrons. Both Simonsen and Dempster felt that it was likely that the cells originated from the grafted organ and were in fact a graft-against-host reaction [5, 6]. Subsequently, using a newly developed isotope labelling technique it was shown by Porter and Calne that most of the infiltrated cells came from the recipient [7].

At the time that these experiments were being performed by Simonsen and Dempster in canine renal allografts, Peter Medawar (Fig. 2) and his colleagues had studied the biology of rejection of skin grafts in rabbits and mice. The first set of grafts became infiltrated with leucocytes after a few days, the graft becoming necrotic after 7-10 days. A second set of grafts from the same donor were usually destroyed immediately and never achieved a capillary circulation. They were called “white grafts”. The immune nature of skin graft rejection was proved beyond doubt by Medawar’s group [8], and from their experiments it seemed likely that kidney grafts between identical twins would behave like skin grafts between identical twins and, provided the surgery was satisfactory, would be accepted without any immune reaction. From this scientifically established basis reciprocal skin grafting should differentiate identical from non-identical cattle twins, and Medawar and his colleagues were confident that this would be straightforward. However, they were astonished and presumably initially disappointed when the non-identical cattle twins accepted skin grafts in the same way that grafts were accepted between identical cattle twins [9]. They became aware of studies of non-identical cattle twins by Ray Owen who had observed that non-identical cattle twins frequently had blood groups of more than one type, circulating in apparently healthy animals [10]. This would be equivalent to a human having some red cells Group A and some Group B, which was know not to occur because of natural antibodies. Owen described the unusual status of their red cells blood groups as “chimeric” from the fanciful resemblance to the mythical ancient Greek animal with organs derived from different species (Fig. 3).

Medawar and his colleagues, Billingham and Brent, then set about performing a series of carefully controlled experiments between inbred strains of mice. The individuals of each strain after many sibling matings would be regarded as identical or “isologous” individuals, so skin grafts were accepted between members of each inbred strain. However, grafts from a given strain transplanted into individuals of a different strain would be rejected, by what was later called the “allograft” reaction.

Based on these observations in the cattle twins Medawar’s group found that injecting cells from one in-bred strain into the foetus of another strain, although a formidable technical achievement, resulted in some survivors, which were then rendered “tolerant” to grafts from the strain that donated the tissue (Fig. 4) [11]. They later found that this tolerance could also be reproduced with neonatal animals, where the technical challenges were still grave but less demanding than in the foetus. This discovery of “specific immunological tolerance” was awarded the Nobel Prize in Medicine or Physiology and was a fundamental advance in immunology and also raised the practical question of whether the plasticity of the developing foetal immunological system could be reproduced in an adult, at least temporarily while a graft was performed, although it would be important that normal immunity would later be restored. Another factor of importance observed by Medawar’s group was that if lymphocytes were included in the donor inoculum they could react against the recipient causing a wasting illness which they called “runt disease” [12]. This was an example of a graft-versushost reaction, which was subsequently recognized to be extremely important in bone marrow transplantation, and also relevant in some organ transplants, particularly the liver where many lymphocytes are transplanted together with the donor liver.

ig. 4. Diagram of immunological tolerance experiments by Billing Brent and Medawar 

In the early 1950s David Hume performed a series of carefully observed clinical kidney grafts, joining the renal artery and vein to the femoral vessels of the recipient, bringing the ureter through the skin [13]. Despite no serious attempt to impair the immunity of the recipients, some of the grafts functioned and one continued to produce urine for nearly five months. When it failed the kidney was found to have both cellular infiltration and severe arteriolar narrowing typical of what later was called “chronic allograft rejection”. The investigators wondered if these somewhat less severe rejections in human kidneys than those observed in animal experiments was due to the fact that the patients all suffered from uraemia, which was both generally debilitating, but also possibly impaired the normal activity of the immune system.

Concurrently, experimental studies were also performed at the Peter Bent Brigham Hospital in Boston by the departments of surgery under Professor Francis Moore and medicine under Professor George Thorn. The surgical experimental lab was headed by Joseph Murray, a plastic surgeon who had a background in very intricate surgical correction of dreadful facial deformities (Fig. 5). He brought his skills to the laboratory and developed an improved surgical technique of kidney transplantation in dogs, in which the renal artery and vein were joined to the iliac vessels and the ureter implanted into the bladder, avoiding the discomfort of a urinary fistula with the concomitant danger of ascending infection. Professor Rene Kuss pioneered the technique of pelvic renal transplantation clinically in Paris in 1953 when a kidney graft from a mother to son implanted using the pelvic site approach functioned 23 days [14]. This was an important advance in providing a surgically acceptable procedure.

Fig. 5. Painting by Joel Babb (1996) of first identical twin transplant in Boston 1954 

Early Clinical Implementation

In 1954, a patient with renal failure was referred by his doctor to Dr. Merrill, a nephrologist, in Dr. Thorn’s Department with an accompanying note saying that “you may be interested to know that this patient is one of identical twins and this could be relevant to your management”, raising the possibility that a kidney transplant from the patient’s identical twin. After careful evaluation of the ethical aspects and also a demonstration that the twins were in fact identical by accepting reciprocal skin grafts, the first identical twin transplant was performed by Dr. Murray and his colleagues at the Peter Bent Brigham Hospital and was a spectacular success [15] (Fig. 6). It showed that as in animal experiments but also in man, if immunological rejection could be avoided, the surgery could produce an excellent long-term therapeutic result for the recipient and also the unilateral nephrectomy in the donor would not lead to long-term harm. For this and his subsequent work, Joseph Murray was awarded the Nobel Prize in Physiology or Medicine in 1990. Incidentally, the first twin donor survived for more than 50 years in good health, and served as the leading edge of follow-up regarding the safety of living donation.

In certain circumstances the original autoimmune cause of renal failure in the recipient recurred in the transplanted kidney, leading to its demise despite (or perhaps because of) being derived from an identical twin [16], and this outcome impelled the search for means of impairing host immunity. In studies on bone marrow transplantation it had been shown that the immune system of rodents could be eliminated by a lethal dose of total body X- irradiation and animals could be rescued by injection of autologous bone marrow from the same strain. The bone marrow cells given intravenously homed to the bone marrow of the recipient and populated, not only the blood-forming elements, but also the lymphoid cells in the lymph nodes and spleen where they could restore immunity [17]. If the bone marrow was not autologous there was danger that the transplant would fail or if partially accepted, could result in a fatal graft-against-host reaction. Later developments in bone marrow transplantation became possible using less severe non-ablative conditioning of the recipient than the original total body irradiation and has proved to be therapeutically successful, and even the graft-against-host reaction has been harnessed as a graft against leukaemia [18, 19].

The success of experimental and clinical bone marrow transplantation following total body irradiation led to hopes that similar conditioning might be effective in recipients of kidney grafts. There was one encouraging result in the dog [20] but unfortunately with the exception of two kidney grafts between nonidentical twins, one at the Peter Bent Brigham Hospital and the other in Paris, all the attempts at total body irradiation failed with disastrous results, rejection not being controlled and overwhelming sepsis becoming a common terminal event [21, 22]. To reduce the toxicity of total body irradiation, repeated small doses of irradiation to the spleen and lymphoid organs was developed by Slavin and Strober in Stanford [23], a technique that continues to be investigated in the pursuit of clinical tolerance.

In the late 1950s it was clear that an alternative superior method would be needed to condition the recipients of kidney grafts more safely, and an important pointer was the demonstration that the anti-leukaemia thiopurine drug, 6-mercaptopurine, would prevent rabbits challenged with foreign protein antigens from producing antibodies. This ef- fect persisted after the 6-mercaptopurine treatment had been stopped and was described by the authors, Schwartz and Dameshek in 1959, as “drug-induced immunological tolerance” [24]. 6-mercaptopurine was then investigated in London at The Royal College of Surgeons of England and in Richmond, Virginia as an immunosuppressant in dogs with renal allografts, resulting in prolonged allograft survival but not tolerance [25, 26]. However the effect was superior to total body X-irradiation. There was a high incidence of infections caused by the severe impairment of immune reactions. Hitchings and Elion, who had synthesised 6-mercaptopurine, provided a number of experimental compounds that they felt were worth investigating as possibly having a better therapeutic indices than 6-mercaptopurine. One of these agents, azathioprine, was found experimentally to be slightly superior to 6-mercaptopurine and became an anchor drug for a landmark series of animal experiments and subsequently for the next phase of clinical immunosuppression which was commenced at the Peter Bent Brigham Hospital [27]. Initial clinical results were disappointing and it was not until corticosteroids were added to the immunosuppressive regimen that some successes were obtained in allografts between unrelated individuals [28]. Azathioprine remains indicated for transplant immunosuppression. 

Steroids had previously been investigated by Medawar and Dempster, but alone were not very effective. However, when combined with azathioprine, better results were obtained. Tom Starzl carefully documented this in Denver, in recipients of renal allografts. Goodwin had already shown that a bolus of steroids could restore function, at least temporarily, to a kidney allograft that was undergoing acute rejection [29, 30].

With day-to-day monitoring of patients and adjustment of drug doses to try and find a level that would prevent rejection without severe toxicity, some 50% of renal allografts were functioning at a year, but failures were a severe burden for the patients, their relatives and the surgeons involved. Nevertheless, during this phase techniques of experimental heart transplantation were developed by Lower and Shumway in Stanford [31]. Additionally, Starzl in Denver and Francis Moore at the Peter Bent Brigham in Boston each developed successful surgical techniques for transplanting the liver [32, 33]. Experimentally head and limb transplants were performed by Demikov in Moscow, but at that time these were little more of a surgical curiosity rather than a serious move forward towards clinical application [34].

It became apparent that transplants between close blood relatives who were not twins had better results than between unrelated donors. The basis for variation was correlated with tissue groups, which were gradually becoming clarified by Dausset, Payne, Van Rood and Terasaki [35-38]. These human leucocyte antigens (HLA) were separate from blood groups, the typing of which also was required to avoid immediate graft failure due to preformed antibodies against red blood cells groups.

Starzl performed the first clinical liver transplants in 1963 [39]. However, the early failure of these grafts and the demise of the patients led to Starzl imposing a moratorium until 1967 when he recommenced a liver transplantation programme at the same time Barnard performed the first clinical heart transplant [40, 41]. The media excitement towards the heart transplant was unprecedented in medical history and led to unfortunate consequences since all over the world cardiac surgeons attempted clinical cardiac transplantation “to join the club”. This was extremely worrying because most of the surgeons had no background knowledge on the biology of transplantation and the difficulties of prescribing immunosuppressive therapies.

Using aziothioprine and steroids the results of cardiac and liver transplantation were poor, but a few patients did very well. Many other agents and procedures were investigated to try and improve immunosuppression. They included total drainage of lymph from the thoracic duct and ex vivo irradiation of the kidney and circulating blood. These procedures were unsuccessful, but the concept of raising antibodies against human lymphocytes proved to be more promising. This had first been investigated experimentally by Woodruff and colleagues in Edinburgh in organ grafts after a demonstration of effective antilymphocyte serum produced in rodents to prolong skin grafts [42]. The antilymphocyte antibodies were polyclonal, that is they reacted against many different epitopes that were generated when lymphocytes or thymocytes were injected into a different species, for example the horse and rabbit. These antibodies were difficult to purify and tended to vary in efficacy and toxicity from batch to batch, but some were very powerful, refined rabbit anti-human thymocyte antibody is still used clinically in patients [43].

The Modern Era of Immune Management

In 1978 Borel, an immunologist working in Sandoz laboratories in Basel, Switzerland, described the immunosuppressive effects of a fungal cyclic peptide, cyclosporine, which was being investigated as a possible antibiotic [44]. Its antibiotic properties were weak but its immunosuppressive activity, both in vitro and in vivo with skin grafts in mice was impressive. On the basis of Borel’s observations we, and workers at Northwick Park, investigated cyclosporine in rats transplanted with heterotopic cardiac allografts and found cyclosporine to be extremely ef- fective [45, 46]. Our studies were extended to canine renal allografts and orthotopic cardiac allografts in pigs. In these species, and later in the rabbit, cyclosporine was shown to be a powerful immunosuppressant with few side effects [47]. However, when it was first used in clinical renal transplants it was found to be remarkably nephrotoxic, a property that had not been suspected in the animal experiments [48]. The nephrotoxicity was particularly severe as the dosage used in the first clinical trials was based on the animal experiments and found later to be much too high. Cyclosporine proved to be a watershed in immunosuppression, with the one-year functional survival of renal allografts increased from 50 to 80%. This early improvement changed the attitude of the medical profession towards organ transplantation that previously had been extremely sceptical, and as a result there were only approximately 10 units worldwide seriously doing clinical organ transplants. After the introduction of cyclosporine there were, within a few years, more than 1000 centres and the anticipated shortage of organ donors suddenly became a major consideration, which has escalated ever since.

From Japan the streptomyces-derived compound, tacrolimus, was developed by the Fujisawa Company and shown by Ochiai to prolong experimental graft survival at a very low dosage [49]. After early experimental organ allografts in different species tacrolimus was used in clinical organ transplantation and fully and exhaustively investigated by Starzl’s group in Pittsburgh [50]. Tacrolimus has a similar nephrotoxic effect to cyclosporine but the hirsutism and gum-swelling, which were the common side effects in cyclosporine-treated patients, did not occur in patients treated with tacrolimus.

The production of monoclonal antibodies by Kohler and Millstein in 1975 provided an agent with a single molecular target [51]. This was quickly exploited for use in transplantation, with the development of OKT3, a murine origin monoclonal antibody specific for the CD3 determinant on T-cells. This agent effected prompt albeit transient reductions in peripheral T-cell counts and was shown to reverse established acute rejection [52]. In 1986, OKT3 became the first monoclonal antibody approved for use in any human disease, and while its side effect profile, clearance by a mouse-specific antibody response, and the emergence of other more tolerable therapies, eventually led to its withdrawal from the market, OKT3 served as a proof-of-concept for the promise of monoclonal antibody therapy in medicine in general. Similarly, the concept of humanization, that is genetic engineering of an antibody to make it largely composed of human structures to avoid a neutralizing antibody effect, was first launched in transplantation with the development of daclizumab [53]. As with OKT3, a completely new therapeutic approach first found its way into the clinic through transplantation. This drug also has been removed from modern practice, but others now find their way into our field through off-label use. Conceptually import in this regard derives from the work of Waldmann and Winter who developed the lymphocyte specific humanized monoclonal antibody Campath 1H or alemtuzumab, an extremely powerful antilymphocyte antibody that eliminating lymphocytes almost completely from the circulation within a few hours [54]. It was developed for the treatment of chronic lymphatic leukaemia but was shown to be a valuable induction agent in clinical kidney transplant patients, allowing maintenance immunosuppression to be reduced to a significantly low level, which eliminates most of the toxic side-effects of maintenance drugs. This concept of powerful almost or “prope” tolerance antilymphocyte induction therapy followed by very low maintenance does not generally result in tolerance, but is probably currently the best available treatment for recipients of organ grafts [55, 56].

It has been known from the early experimental liver grafts in pigs and later in rodents, that liver grafts were less severely rejected than other tissue and sometimes were accepted long-term as an “operational” tolerance in animals not given any immunosuppression. The transplanted liver often underwent biochemical and histological rejection, which recovered spontaneously [57-59] (Fig. 7). These observations were a background to “experiments” performed by patients in Pittsburgh who were non-compliant in taking immunosuppression, without telling their doctors. Some of these patients with liver transplants have survived for more than 20 years without any immunosuppression and justifiably would be regarded as operationally tolerant. Patients in whom immunosuppression was deliberately stopped or weaned because of infection or as a policy to see if they were tolerant produced variable results. Some patients accepted their grafts without deterioration indefinitely, but others developed rejection and had to return to immunosuppression. Even an extremely low dose of immunosuppression may be important in recipients of organ grafts, stopping a very low dose may lead to rapid rejection which may be difficult to reverse [60, 61].

A more biological approach to immunosuppression has been studied for some years based on successful murine experiments. Engagement of foreign tissue with the recipient immune system involves not only recognition and reaction to antigenic epitopes, but also a complicated secondary signal that binds the cells presenting the antigen to the immune reactive cells. The second signal has been studied in great detail and various methods of blocking the second, now costimulatory, signal have shown encouraging results experimentally and have now been investigated in the clinic [62].

Ethical Challenges

In the past 50 years organ transplantation has come a long way from a theoretical, fanciful concept to a fully established practical therapy. There are still many biological obstacles to be investigated and overcome, particularly recurrent disease in the transplanted organ, the development of renal damage and diabetes associated with calcinurin-inhibiting drugs and infection and malignancy, especially lymphoma and skin cancers. All these unsatisfactory features of organ transplants have gradually become understood and various methods of avoiding these side effects and treating them have been developed. Indeed, and in depth understanding of these adverse conditions form the foundation of the knowledge required for the clinical practice of modern transplantation, and is approached to some degree in most chapters in this text. Organ grafting requires surgical expertise but also an ethical framework of compassion and care (Fig. 8). The success of organ grafts has raised ethical questions that have emerged like “a can of worms”, totally unexpected by the pioneers of transplantation in the early days. As the results of organ transplants improve, so the demand increases, yet the donor supply does not increase pari passu. There are not sufficient deceased donor organ transplants in any country. Indeed, public opinion is often not in favour of deceased donation nor are some governments prepared to invest in the infrastructure necessary to educate the public or provide the medical facilities necessary for intensive care of potential donors. Spain has been the most successful nation in all areas with deceased organ donation of more than 30 cases per million but with improved treatment of head injuries and less road traffic accidents than previously, the “donor pool” has become reduced [63, 64].

Living donors have been used extensively since the beginning of organ transplantation in identical twins. Usually the kidney transplantation can be performed ethically between related and unrelated family members and liver transplantation from parents to children. However beyond these stipulated cases the ethics of organ donation have been strongly questioned. Recently a child in China sold his kidney without his parents knowing to obtain cash to buy an iPod [65]. Many thousands of patients executed in China had their organs removed for transplantation. The transplant community in the West condemns this practice as unacceptable on a variety of grounds, including the use of organs to generate income from rich foreign “organ tourists”. Pressure can be put on individuals to donate within a family and relations of the patient may feel forced to acquiesce or have a terrible guilt feeling if they refuse. Attitudes to donation between donor and recipient may change. A New York surgeon who had given a kidney to his wife, later divorced her and was awarded considerable damages in consideration of his previously considered altruistic gift [66]. Liver transplantation from a living adult donor to another adult has risks that are very difficult to explain to the prospective donor. Not only is there a high likelihood of prolonged morbidity, but there is a possibility that organ donation will cause the donor to lose his or her job and mortality as a result of the donor operation is high enough to be considered a significant risk. Five partial liver donors to adults have been reported to have developed liver failure themselves, four died and one was rescued by a transplant [67]. Rich patients may buy organs illegally. Seldom do the rich donate organs to poor recipients.

It is unlikely that the ethical difficulties will be easily overcome, but defining them is the first step. In the middle 1960s attempts were made to transplant organs from animals to man. A variety of well-documented kidney transplants were reported from New Orleans, Denver, and Richmond, Virginia and there were also sporadic attempts at other organ xenografts. To date none have been successful longterm apart from one kidney transplant from a chimpanzee to a patient in new Orleans, which functioned for nine months, eventually succumbing to chronic rejection [68]. A great deal of effort has been put into studying xenograft reaction and defining the barriers. However, despite intense and expensive experimentation, each barrier appears to be rather like an opaque hazard in a steeplechase where it is necessary to overcome the first barrier to see the next one and currently we do not know how many barriers there are or even if the race can be won.

Summary

In a brief period of less than 60 years, transplantation has emerged from its humble origins as an experimental curiosity to being an accepted means of life saving therapy for most end organ diseases. Its success has become increasingly expected, and its implementation increasingly seen as routine. Survival of patients with cadaveric kidney and liver grafts for more than 40 years shows the therapeutic potential of clinical organ grafting as a life-saving treatment with restoration to a normal long-term quality of life (Figs. 9-11).

In the foreseeable future, despite (or perhaps as a result of) exceptional advances in overcoming the surgical and immunological barriers to transplantation, the shortage of organ transplants will remain, and it is incumbent on the transplant community to explain honestly the situation to the public and their governments, and to face the unwelcome fact that not everybody who might benefit from a transplant will receive one, this is especially true in poor nations. It is hoped that as one consumes the specifics of the expansive practice that is modern day organ transplantation, they will recognize the common thread that moves through it from fundamental biology and discovery to similarly fundamental ethical concerns that define our humanity. In doing so, the student of transplantation will best appreciate the privilege and responsibility that this field imparts upon them (Fig. 12). 

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