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.
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 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 Table1) 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.
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 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 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.
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 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 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 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 serum-based 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 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 half-century 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 bacteriocidal 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 antibody-mediated 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 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 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-year-old 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 well-functioning autotransplanted kidneys ultimately failed 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 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 living-related 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 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
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 end-stage 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. Antigen-independent, donor-associated conditions such as brain 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.
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