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Transplantation, the removal or partial detachment of a part of the body and its implantation to the body of the same or a different individual, has fascinated mankind for centuries. Legends of transplantation are recorded in the early written histories of both Eastern and Western cultures. Homer, in his Iliad, describes the monstrous Chimaera, a remarkable creature of transplanted animal parts created by the gods. This mythical hybrid animal had the heads of a lion, a goat, and a serpent. All three of its heads breathed fire. (35) The term chimaera is now used in transplantation to describe individuals who possess hybrid characteristics, such as the circulating cells of both donor and recipient after bone marrow transplantation.
A Chinese document written in approximately 300 B.C. contains this legendary account of transplantation: ""One day two men, Lu and Chao, called on the surgeon Pien Ch iao. He gave them a toxic drink and they were unconscious for three days. Pien Ch iao operated and opened their stomachs and explored the heart; after removing and interchanging their organs he gave a wonderful drug and the two men went home recovered."" (63)
The legend of Cosmas and Damian describes transplantation as one of the miraculous feats of these two medical martyrs. Born in Arabia in the third century A.D. and trained in medicine in Syria, Cosmas the physician and Damian the surgeon performed numerous miraculous healings until their martyrdom in 287 A.D. by decapitation. The miracle of the black leg is said to have occurred posthumously in approximately 348 A.D. While an elderly parishioner with a gangrenous, cancerous leg lay sleeping in the Basilica of Cosmas and Damian, the saints came to him and removed the diseased leg with a saw. They replaced the destroyed tissue with the fresh leg of a Moor buried that same day in the cemetery of Saint Peter. The new leg was attached at the thigh and ointment applied to the site. The parishioner awoke to find himself free of pain and able to walk on his new healthy black leg. (37) Attempts at transplantation during the Middle Ages did not always end so successfully. Tragically, in 1492 two boys were bled to death in a vain attempt to save the life of Pope Innocent VIII by means of transfusion of young blood. (63)
The oldest evidence of grafting that could have been of some therapeutic benefit is observed in the remains of trephined prehistoric skulls. The trephine holes were usually small, but in a Bronze Age skull a rather large defect evidently was filled by reimplanting the removed fragment. (30) In this specimen, the cut margin showed no sign of healing, so the operation may have been fatal. Recovery from primitive skull trephination is well documented, however, both archeologically and in studies of primitive peoples in modern times, and it is conceivable that such trephination was sometimes therapeutically effective.
Ancient Hindu surgeons described methods for repairing defects of the nose and ears using techniques of grafting similar to those used in modern times. The following technique for nasal reconstruction is quoted from a translation of the Sushruta Samhita, a document written about 700 B.C. (7) :
Now I shall deal with the process of affixing an artificial nose. First the leaf of creeper, long and broad enough to fully cover the hole or the severed or clipped off part should be gathered; and a patch of living flesh equal in dimension of the preceding leaf, should be sliced off from down upward from the region of the cheek and, after scarifying it with a knife, swiftly adhered to the severed nose. Then the cool-headed physician should steadily tie it up with a bandage decent to look at and perfectly suited to the end for which it has been employed. The physician should make sure that the adhesion of the severed parts has been fully effected and then insert two small pipes into the nostrils to facilitate respiration and to prevent the adhesioned flesh from hanging down. After that the adhesion part should be dusted with the powders of sappanwood, licorice-root and bayberry pulverized together; and the nose should be enveloped in cotton and several times sprinkled over with a refined oil of pure sesamum....As soon as the skin has grown together with the nose, he cuts through the connection with the cheek.
This Indian method was lost to Western medicine until 1794 when English surgeons stationed in India described nasal reconstruction as they had seen it performed by an Indian surgeon, the technique quite similar to that described more than 1000 years earlier. (62)
A new Western tradition of transplantation surgery arose during the Renaissance in Bologna. The sixteenth century anatomist and surgeon Gasparo Tagliacozzi developed his technique for reconstruction using a flap of skin from the inner aspect of the upper arm. He carved the flap of skin in the shape of the patient s nose and then stitched it to the forehead and inner surface of the cheek, leaving a slender attachment to the arm to maintain blood supply until circulation was re-established from the face. After this painful procedure, the patient had to sit upright with the arm alongside the face and the head turned toward the arm for the next 3 weeks of healing; then the attachment to the arm was severed. Tagliacozzi was successful in replacing noses cut off in combat or for punishment or destroyed by syphilis. The technique is still in use and is known as the tagliacotian flap or the Italian method. In considering but discarding the idea of grafting tissue donated by another individual, Tagliacozzi made the following remarkable statement: ""The singular character of the individual entirely dissuades us from attempting this work on another person. For such is the force and the power of individuality, that if anyone should believe
The Scottish surgeon John Hunter (1728-1793) is known as the father of experimental surgery because of his pioneering research. Several of his experimental procedures involved transplantation, and some of his specimens are still preserved in the Hunterian Museum in London. Hunter revived the practice of transplanting teeth, which had been done in ancient Egypt, Greece, Rome, Arabia, and pre-Columbian America, as well as by Ambroise Pare of Paris in the sixteenth century. (46) With his crude techniques of transplanting tissues without primary revascularization and without antisepsis, Hunter was unable to distinguish allografts from autografts on the basis of graft survival. About this operation he wrote: ""Success of this operation is founded on the disposition of all living substances to unite when brought in contact with one another, although they are of different structure and even though the circulation is carried in one of them."" (10)
In other animal experiments he successfully autografted and allografted chicken testes and observed that the ends of severed Achilles tendons grew together after suturing. A variety of connective tissue transplant procedures were performed successfully for the first time during the eighteenth and nineteenth centuries. Foremost among these were skin grafts and corneal transplants.
The first well-documented report of successful free autografts of skin was in 1804 by Baronio, who experimented with sheep, although free autografts of human skin may have been used successfully centuries before. (10) (19) (46) (62) In 1822, Bunger reported successful use of a free full-thickness human skin autograft to repair a nasal defect. In 1870, Reverdin reported the observation that small grafts of epidermis on a granulating surface increased in size and grew out to coalesce with adjacent grafts. In 1886, Thiersch, in Germany, described the resurfacing of wounds with large sheets of split-thickness skin. Such grafts are still sometimes termed Thiersch s grafts, although essentially the same procedure was reported 14 years earlier by Ollier in France.
In 1863 Paul Bert, a student of Claude Bernard, reported that autografts, allografts, and xenografts behaved differently. (19) (62) The significance of these observations received little attention, however; nineteenth century authors (including Baronio and Reverdin) generally failed to observe that the results of allografts and autografts of skin were different. Skin allografts were used to some extent clinically, as illustrated in a story by Winston Churchill of his donating a small piece of skin to a wounded fellow officer in 1898. (19) There appear to have been three reasons for the mistaken belief that skin allografts grew permanently, a belief still widely held as late as the third decade of the twentieth century: (1) for a week or more skin allografts are indistinguishable from autografts; (2) it is difficult to distinguish between permanent survival of a small skin graft and ingrowth of adjacent host skin to cover the area of a sloughed graft; and (3) corneal allografts survive permanently.
Corneal xenografts attempted early in the nineteenth century were unsuccessful. A successful corneal allograft between two gazelles was reported by Bigger in 1835 (46) (62) ; but the necessity of using a cornea from the same species was not recognized until the period 1872 to 1880, when successful corneal allografts were reported in animals and in man. Refinements of operative techniques, methods of preservation of grafts, and systems of graft procurement were subsequently developed. From 1925 to 1945, corneal transplantation emerged as a widespread and generally accepted therapeutic practice. (18) (46) (62)
Although important developments in the last half of the nineteenth century, such as the use of ether and other general anesthetics and the acceptance of Lister s principles of antiseptic surgery, were important in the progress of transplantation, organ replacement is a development of the twentieth century. Transplantation of vascularized organs, including the kidney, liver, heart, lung, pancreas, and intestine, was first made possible when techniques for vascular anastomosis were developed.
The first long-functioning renal transplant was reported by Ullmann in March 1902. He transplanted kidneys into dogs using magnesium tube stents and ligatures to make the vascular anastomoses to the carotid artery and internal jugular vein in the neck. (59) That same year the French surgeon Carrel reported his new technique of suturing blood vessels together using triangulation and fine silk suture material (Fig. 20-1) . (12) His revolutionary technique was rapidly applied to the problems of organ transplantation. Between 1902 and 1912, Carrel and Guthrie of Chicago performed a large series of animal transplantation experiments, including the transfer of blood vessels, kidneys, hearts, spleens, ovaries, thyroids, extremities, and even the head and neck. In 1905 in his preliminary communication entitled ""The Transplantation of Organs"" Carrel stated:
This operation consists of extirpating an organ with its vessels,
of putting it in another region, and of uniting its vessels to a neighboring
artery and vein. If the organ is replaced in the same animal from which it
was removed the operation is called an autotransplantation. If it is placed
in another animal of the same species it is called a homotransplantation, while if it is placed into an animal of a
different species, the operation is called a heterotransplantation. (13)
Although the terms defined by Carrel are still used occasionally, the preferred nomenclature is now allotransplantation (allograft) for transplants between nonidentical members of the same species and xenotransplantation (xenograft) for transplants between members of different species
Figure 20-1 Carrel s technique of vascular anastomosis. Shortly after Alexis Carrel
reported his new technique of suturing blood vessels together using triangulation
and fine silk suture material, he applied the method to the transplantation
of blood vessels, hearts, spleens, kidneys, and extremities. (From
Carrel, A.: La technique operatoire des anastomoses vasculaires et
la transplantation des visceres. Lyon Med., 98:859, 1902.)
Carrel did not understand the biologic basis for differences in graft outcome among the various types of grafts he attempted, although by 1910 he recognized the problem of rejection:
Should an organ, extirpated from an animal and replanted into its owner by a certain technique, continue to functionate normally, and should it cease to functionate when transplanted into another animal by the same technique, the physiological disturbance could not be considered as brought about by the surgical factors. The changes undergone by the organ would be due to the influence of the host, that is, the biological factors.
Elucidation of the biologic factors hypothesized by Carrel required several decades and is, in fact, continuing today. A few of the milestones in transplantation immunology are cited.
Although the immunity theory of graft rejection was postulated by several authors during the first decade of the century, a number of other theories were held by prominent authorities, such as Loeb. The immunity theory was questioned largely because there was no direct evidence that circulating antibody--the traditional hallmark of immunity--was involved in the rejection process. Antibodies had been demonstrated in response to allografts of tumor but not allografts of normal tissues, and attempts to confer allograft immunity passively with serum were unsuccessful. The discovery of cellular immunity, histocompatibility antigens, and immunologic tolerance provided important steps in the understanding of transplant rejection.
In 1914, Murphy reported lymphocytic infiltrates in host tissues surrounding
rejecting transplanted tumors. (19)
(62)
He postulated that the small lymphocyte was responsible for that rejection,
and he used radiation and treatment with benzene to modify the process. The
role of cellular immunity (lymphocytes),
as distinguishable from humoral immunity
(circulating antibody), was not firmly established, however, until experiments
were performed in which certain forms of immunity were observed to be transferable
|
Recent Nomenclature |
Older Nomenclature |
Relationship of Donor and Recipient of Graft |
|---|---|---|
| Autogeneic graft | Autograft | Same individual |
| Isogeneic graft | Isograft |
Same species and genetically identical |
| Allogeneic graft | Homograft |
Same species but not genetically identical |
|
Xenogeneic graft |
Heterograft | Different species |
In 1903, Jensen observed that a second graft did not survive as long as the first when a mouse received two grafts of a tumor separated by an interval of several days, and he suggested that immunity was responsible for the difference. This effect of more rapid rejection of a second graft was not always observed with transplants of tumor, however. Under certain conditions survival of the second graft was prolonged. Casey, in 1932, termed the latter phenomenon enhancement, and Kaliss, in 1953, reported that enhancement is transferable to normal animals by injections of serum. (62) The effect was subsequently demonstrated to be due to an immunoglobulin, and enhancing or blocking antibodies have been used experimentally to prolong the survival of nonneoplastic as well as neoplastic tissues.
The second-set phenomenon in human skin graft recipients was observed by Holman while treating burn patients at the Johns Hopkins Hospital. He reported in 1924 that a second group of pinch grafts from the same donor were rejected more rapidly than the first and that ""the destroying agency is specific for each set of grafts."" (34) He postulated that each group of grafts developed its own antibody. In 1932, Shinoyi, in Japan, described the specificity of the second-set phenomenon. Gibson and Medawar, working in England in 1943, reported similar observations with burn patients, and use of the term second set dates to this report. (10) (19) (42) (62) In subsequent controlled experiments with rabbits, Medawar demonstrated the immunologic specificity of the phenomenon, which was observed uniformly only when the same donor was used for both the first set and the second set of grafts. Medawar also contrasted the histologic characteristics of first- and second-set rejections, the first-set rejection being predominantly a cellular event, whereas both cellular and humoral mechanisms are involved in the rejection of the second set of grafts.
When immunity, both cellular and humoral, had been established as the cause of graft rejection, study was focused on the antigens that both stimulated graft rejection and were the targets of the ensuing immune response. The antigens responsible for graft rejection and the genetic control of these antigens have been most extensively studied in the mouse. The influence of genetic factors was documented by Jensen, Tyzzer, and Little in the first two decades of the century. (46) (62) In 1948, Gorer, Lyman, and Snell described H-2 as a genetic locus controlling strong histocompatibility antigens in the mouse. Subsequently, this locus and numerous minor histocompatibility loci were characterized in great detail.
The definition of the major histocompatibility locus of man, HLA, is intertwined with the evolution of typing and cross-matching for human blood donor selection. The work of Landsteiner during the first four decades of this century with erythrocyte ABO and Rh antigens was necessary for blood banking and transfusion, which were done extensively during and after World War II. The development of blood transfusion contributed to progress with the problem of graft rejection in three respects. First, the A and B erythrocyte antigens are widely distributed in tissues and are transplantation antigens that must be considered in the selection
The serologic identification of transplantation antigens began in 1952 when Dausset discovered a leukocyte antigen responsible for transfusion reactions. (11) Payne found in 1958 that antileukocyte antibodies were frequent in the sera of multiparous women, thus establishing a rich source of reagents for tissue typing. The new system of tissue matching was first used to select appropriate donors and recipients by Hamburger of Paris. (31) In 1964, Payne reported the first clear evidence that these leukocyte antigens segregated in families as a genetic system. Whereas the original serologic identification of transplantation antigens was done by leukoagglutination, Terasaki, in 1964, introduced a much more sensitive and specific microlymphocytotoxicity test. (57) Definition of the HLA system, the major histocompatibility gene complex of man, has followed a series of international workshops, the first of which was organized in 1964 by Amos at Duke University. A major advance that same year was the discovery that lymphocytes from potential donors and recipients, when mixed together in tissue culture, undergo a vigorous proliferative response. This reaction, termed a mixed lymphocyte culture (MLC), became, along with microlymphocytotoxicity, a major approach for histocompatibility testing. (11)
The chimaera, an organism carrying living tissues of two or more genetically different individuals, exists not only as a creature of Greek mythology but also naturally in dizygotic cattle twins. Owen, in 1945, reported that each of such twins has two different types of erythrocytes, and he postulated that the marrow of each individual had become populated by cells of both in utero when the circulation of the two placentas was mixed. (45) Owen successfully exchanged skin grafts between the cattle twins, and in 1955 Simonson reported that kidneys as well as skin could be readily transplanted between them. In 1953, Dunsford discovered a human twin carrying both A and O erythrocytes, but the other member of the pair died in infancy. In 1959, Woodruff and Lennox reported successful exchange of skin grafts from dizygotic human twins showing blood chimaerism with types A and O. (42) (62) Allografts of skin placed on a chimaera from donors other than the chimaeric mate were rejected in the normal manner. Thus, a natural chimaera is specifically nonreactive to the tissue antigens of its chimaeric mate. Such nonreactivity specifically limited to particular antigens is termed immunologic tolerance. In contrast, immunosuppression is nonspecific suppression of immune responses to antigens generally. The most common example of naturally occurring tolerance is the normal state of nonreactivity to self antigens, that is, to the antigens of one s own body. Autoimmune diseases are the consequence of abnormal reactivity to self antigens. Burnet conceived recognition of self antigens as one of the aspects of embryologic maturation of the immunologic system. (42) (62)
The creation of states of acquired tolerance (i.e., induced specific immunologic tolerance) has been achieved largely by exposure of embryonic, fetal, or early postnatal hosts to grafts that the normal adult animal would reject. Before tolerance was defined immunologically, Murphy, in 1912, observed that rat sarcomas grew on chicken embryos but not in mature chickens, and he noted that the chick acquired the adult capacity to reject the tumor approximately 5 days after completion of shell life. (9) (62) In 1929, Danforth and Foster reported successful skin grafts between newly hatched Rhode Island red and Plymouth Rock chicks (Fig. 20-2) . (42) In 1950, Cannon and Longmire reported similar observations, but they noted additionally that the percentage of take was only 1% if the grafts were performed on chicks 3 days old and was nil at the age of 14 days. (42) (62) A landmark article in the understanding of transplantation immunology appeared on October 3, 1953, when Billingham, Brent, and Medawar reported their experiments on ""actively acquired tolerance of foreign cells."" (8) They systematically studied the phenomenon of actively acquired tolerance between inbred strains of mice of various ages before and after birth. It became clear that the barrier between self and non-self could be overcome if the exposure to alloantigens occurred in the neonatal period. Grafts established on the fetus survived permanently, and the host was tolerant of other grafts from the donor strain; grafts performed more than 1 or 2 days after birth were rejected, and the rejection of subsequent grafts from the donor strain was accelerated. These authors also reported breaking tolerance, that is, reversing tolerance and terminating the chimaeric state, by injecting lymphoid cells of normal adult host-strain mice into tolerant animals. The reversal of the tolerant state in these experiments was marked by the sloughing of long-established grafts of skin and other tissues from the donor strain.
Animals rendered tolerant prenatally or neonatally were normal except for being chimaeras and for being specifically nonreactive to antigens of the donor. Many subsequent studies have been directed toward the objective of inducing tolerance in the adult by methods that would be applicable to therapeutic transplantation in man. Lasting tolerance has been produced in adult mice that were temporarily immunosuppressed at the time of initial exposure to donor antigens, but tolerance is readily produced by this means only if the donor-recipient incompatibility is weak. Immunity, not tolerance,
Figure 20-2 Tolerant chickens. In 1929 Danforth
and Foster successfully transplanted skin between newly hatched Plymouth
Rock (light) and Rhode Island red (dark) chickens. Such grafts take shortly
after birth, but not 2 weeks later, and provide an example of actively acquired
tolerance. (From Moore, F. D.: Give and Take: The Development of
Tissue Transplantation. Philadelphia, W. B. Saunders, 1964.)
Total-body irradiation had been used extensively to prevent rejection of grafts in experimental animals before it was used in the first successful human allografts from living, related donors in Paris and in Boston. (42) However, in the 4 years between March 1958 and March 1962, of 12 potential recipients at the Peter Bent Brigham Hospital who were subjected to total-body x-irradiation with or without marrow infusion, only 1 survived. Although the one patient with a successful allograft lived for 25 years, irradiation as an immunosuppressive agent was judged ""too blunt, nonspecific and unpredictable."" (43) Schwartz and Dameshek (50) reported in 1959 that 6-mercaptopurine blocked the capacity of rabbits to form antibody. The animals could still react with proteins administered before or after the period of 6-mercaptopurine treatment, suggesting an element of specificity in the suppression. Calne and Zukoski independently used the drug successfully for canine renal transplants, and Hitchings and associates developed an imidazole derivative, azathioprine, in 1961 that could be administered conveniently and safely in an oral form. Murray, Hume, and Starzl reported clinical successes with the new drug that same year, thus initiating the modern era of transplantation. (43)
In the 1950s, numerous authors reported the efficiency of adrenocortical steroids in reversing the manifestations of various immunopathologic disease states. In 1963, Starzl reported that prednisone added to azathioprine produced good results in most patients. The following year, Marchioro and associates reported the successful use of prednisone to reverse established manifestations of renal allograft rejection. Antilymphocyte serum was demonstrated by Woodruff and Anderson in 1963 to prolong skin allograft survival in rats and was used clinically in 1966 by Starzl. (10) (43) The immunosuppressive properties of cyclosporine were discovered by Borel in 1972, used by him in animal studies in 1974, and used clinically by Calne in kidney transplantation trials in 1978. (9) Whereas the indiscriminate use of immunosuppression in the 1950s and 1960s employed modalities that affected cells and tissues in addition to the immunocompetent cells responsible for allograft rejection, cyclosporine and, subsequently, monoclonal antibodies allowed modulation of more defined populations of the involved cells. Although alloantigen-specific immunosuppression remained an elusive goal of transplantation research, cyclosporine markedly improved the results of liver, heart, and heart-lung transplantation, making them for the first time broadly applicable as therapies for end-stage organ failure.
With the advent of chemical immunosuppression, the brief but exciting history of clinical transplantation began. For the first time, several vascularized organs were transplanted with regular success. Foremost among these was the kidney.
The technical barriers to kidney transplantation were overcome early in the twentieth century by Ullmann (59) and Carrel. (14) In 1908 Carrel wrote: ""It is to be concluded that an animal which has undergone a double nephrectomy in the grafting of both kidneys from another animal can secrete almost normal urine with his new organs, and live in good health at least for a few weeks. This demonstrates that it is possible to re-establish sufficiently functions of transplanted kidneys.""
In 1906, Jaboulay attempted two kidney xenografts from a pig and a goat to the extremities of patients with chronic renal failure. The kidneys failed after only 1 hour. In 1909, Unger attempted a monkey-to-human kidney transplant to save a girl dying in renal failure. The kidney was sutured to her thigh vessels, but no urine was produced. (32) The first human kidney allograft was performed in 1933 in the Ukraine by Voronoy. He transplanted a kidney donated from a head-injured victim to a patient with acute renal failure from mercuric chloride poisoning. Six hours were required to transplant the kidney to the recipient thigh vessels under local anesthesia, and the transplanted organ never functioned. Voronoy reported six unsuccessful human renal allograft attempts between 1933 and 1949. A kidney allograft to the arm vessels was performed by Hufnagel, Hume, and Landsteiner in Boston in 1946. The transplanted kidney functioned transiently until the patient s own kidneys recovered, and she eventually left the hospital fully recovered. (42) Between 1950 and 1953, human kidney allografts were attempted without immunosuppression in Paris and Boston. (32) (41) Most of these kidneys failed immediately, but one transplant recipient of Hume had life-sustaining renal function for several months. Living-related transplantation commenced in 1953 when Michon of Paris transplanted a kidney from a mother to her son, whose solitary kidney had been damaged in a road accident. The kidney functioned for 22 days before it was rejected. (32) In 1954, Murray performed the first renal transplant between monozygotic twins and achieved excellent, long-term function. (43) In March 1958, Murray, in Boston, and Hamburger, in Paris, each performed a series of human kidney allografts using total-body irradiation for immunosuppression. (32) The modern era of immunosuppression had begun, and the subsequent history of renal transplantation paralleled the development of immunosuppressive drugs.
Canine liver grafts were shown to function after transplantation to the pelvis by Welch in 1955. Orthotopic liver transplantation in dogs was attempted by Cannon in 1956 and performed successfully by Moore in 1959. The first attempt at liver allotransplantation in man was made by Starzl at the University of Colorado on March 1, 1963. (52) The 3-year-old recipient with extrahepatic biliary atresia died of hemorrhage on the day of transplantation. Ensuing attempts in Denver, Boston, and Paris were unsuccessful until 1967, when the first extended survival of a human liver allograft recipient was achieved by Starzl. The addition of cyclosporine immunosuppression by Calne in 1978 and then combination therapy with cyclosporine and prednisone by Starzl in 1980, as well as better liver preservation and surgical techniques, improved the prospects for clinical liver transplantation.
Carrel and Guthrie performed the first heart transplant in 1905 at the University of Chicago. (16) They transplanted a canine heart to the neck of another dog and observed rhythmic contraction for 2 hours until coagulation occurred in the cavities of the heart. Mann and associates, in 1933, transplanted canine hearts to the neck with more success. (40) One of their dogs survived 8 days, allowing them to be the first to recognize cardiac allograft rejection. The first clinical heart transplant was performed by Hardy in Jackson, Mississippi, in January 1964. (33) A 68-year-old patient in cardiogenic shock received a chimpanzee heart when the prospective human donor became unsuitable. The small animal heart proved inadequate to take the patient s venous return, and the recipient died after 1 hour. The first successful clinical transplant was performed on December 3, 1967, when Dr. Christiaan Barnard, at the University of Cape Town, transplanted the heart of a young man to a 54-year-old patient with a heart irreparably damaged by repeated myocardial infarction. (4) The recipient lived 18 days before dying of gram-negative pneumonia. The historical foundations
In contrast to the success of cardiac allografts, clinical lung transplantation proved much more difficult. The first human lung transplant was performed by Hardy on June 11, 1963, in a patient with chronic lung disease and carcinoma of the left lung. The patient survived 18 days before dying of renal insufficiency. Because of the difficulty of finding suitable donors, bronchial anastomotic complications, and allograft rejection, only 38 lung transplants were performed in the first 15 years of clinical experience. (60) The longest survivor was a 23-year-old sandblaster with micronodular silicosis who lived 10 months after lung allotransplantation. (21) The tracheobronchial anastomotic complications were initially overcome by simultaneous transplantation of the lungs and heart, a procedure first performed by Reitz and associates at Stanford in 1981. (49) Single-lung and eventually double-lung transplantations without the heart were made possible by technical advances pioneered by Cooper and colleagues in Toronto. (58)
The first clinical pancreatic transplant was performed by Williams. (23) His patient, a 15-year-old boy, died in coma 3 days later. Work in this area was sporadic and unsuccessful until 1922, when Banting and associates corrected the hyperglycemia of human diabetes mellitus by injection of bovine pancreatic extract. (3) However, clinical application of whole pancreas transplantation in a systematic manner was not to occur for more than 40 years. In 1970, Lillehei published the first cases in the extensive University of Minnesota series of clinical pancreatic allotransplants that began in 1966. (39) In the original 14 cases of pancreaticoduodenal transplantation, four patients and one graft survived more than 1 year, and one recipient was still alive in 1984. The same institution reported the first large series of human islet allografts in 1977. However, none of 20 islet allografts led to insulin independence, and only 3 of 10 islet autografts for chronic pancreatitis led to insulin independence. (44) The historical development of pancreatic islet transplantation is reviewed by Downing. (23)
During the short history of clinical pancreas transplantation, the difficult problem of eliminating or draining the pancreatic exocrine secretions was managed in several ways. Gliedman and associates attempted to anastomose the pancreatic duct to the ureter. (26) Duct ligation was attempted by the same group as well as by Groth in 1976. (29) The technique of injecting the pancreatic duct with a synthetic polymer to block exocrine function was reported by Dubernard and associates in 1978. (24) Free drainage of the duct into the peritoneal cavity was investigated by Sutherland and reported in 1979. (54) However, intractable ascites occurred in some patients, and an overall technical complication rate of 50% mandated reinvestigation of enteric drainage. (54) Bladder drainage, as popularized by Sollinger and associates, (51) produced improved results with combined kidney-pancreas transplants. With the use of the segmental technique and a pancreaticojejunostomy, living-related donor pancreas transplantation began in 1979. (55)
Although autotransplantation of the bowel is among the most frequently used and successful forms of organ transplantation (see Part XII in this chapter), intestinal allotransplantation has been generally unsuccessful. Clinical small intestinal allografting was attempted in several patients after 1967 for bowel infarction, (38) repeated sepsis on total parenteral nutrition, (1) and Gardner s syndrome with recurrent desmoid tumors of the bowel. (25) Even in the case of the HLA identical graft, which survived 76 days, minimal useful bowel function was observed. Rejection, graft-versus-host disease, infection, and high operative mortality historically diminished surgical enthusiasm for intestinal transplantation. The advent of cyclosporine immunosuppression and subsequent potent drugs have reawakened interest in the field. (20) (22) (47)
When the techniques of vascular anastomosis were sufficiently well known to permit successful autotransplantation and allotransplantation, a number of xenogeneic transplants into humans were attempted. Between 1905 and 1910, several workers, including Jaboulay in France and Unger in Germany, performed xenografts but did not document graft function. (32) When the immunologic basis of rejection was established, renewal of interest in clinical xenotransplantation awaited the development of new immunosuppressive measures. After the efficacy of chemical immunosuppression with azathioprine, prednisone, and mitomycin-C was established, Reemtsma and associates, in 1963 and 1964, undertook xenografts in patients in renal failure using kidneys from nonhuman primates. (48) Several of these cases showed satisfactory immediate function, but all were eventually rejected within a few months. When cyclosporine became available for clinical use, human xenografting was again attempted in 1984. (2) A baboon heart was transplanted to a child born with a severe congenital malformation of the heart. Despite intensive immunosuppression, rejection developed and the infant died within weeks of transplantation.
Along with the improved capability of transplanting tissues and organs, interest in preservation and storage of living tissue developed. The structural integrity and the viability of the graft had to be maintained during the interval from removal to implantation. Basically, two approaches were available: (1) methods that reduced or brought to a reversible standstill the need for oxygen and other metabolic requirements and (2) systems that supported active metabolism. Of the several methods that were tried to achieve long-term preservation, including freezing, only hypothermia and organ perfusion are in general use today. In addition, chemical inhibition of metabolism in the form of cardioplegia solution is used for cardiac transplantation and many other open-heart surgical procedures as discussed in Chapter 54
In 1908, Carrel removed an artery from one animal, preserved it with hypothermia for days, and then successfully transplanted it to another animal. (15) The numerous other contributions of Carrel to tissue culture and ultimately organ perfusion were reviewed by Humphries and Dennis in their ""Historical Developments in Preservation."" (36) Using his newly developed media and culture techniques, Carrel was able to maintain chick embryo fibroblasts in continuous culture for more than 25 years! His attempts at organ culture were less successful. With the use of a pump and perfusion apparatus designed by Charles Lindbergh, organs were perfused for 20 to 40 days with normothermic serum. Although some cells remained viable, reimplantation of the organs was not undertaken to test the effectiveness of the preservation system. Maximal preservation of kidneys was approximately 2 days. (17)
A variety of solutions were used for continuous perfusion of organs. Humphries achieved 24-hour dog kidney preservation using continuous perfusion with dilute blood at 10° C. Plasma protein fraction, cryoprecipitated plasma, silicone-gel fraction of plasma, and albumin were all added to electrolyte solutions to improve preservation. Belzer and associates, in 1967, introduced a new pump and perfusate containing lipoprotein-free serum for continuous pulsatile perfusion at 10° C. that enabled him to consistently preserve kidneys for 72 hours. (5) Improved preservation solutions developed by him at the University of Wisconsin extended preservation times of the kidney and ultimately of the liver and pancreas as well. (7)
At temperatures of 0° to 4° C., tissues remain
A natural outgrowth of the capabilities for organ preservation and tissue matching was the development of networks for sharing kidneys on the basis of histocompatibility. For example, in 1968, Hume, at the Medical College of Virginia, in cooperation with Amos, of Duke University, developed an organ-sharing plan to enlarge the potential recipient pool for each new kidney that became available so that better tissue matches between donor and recipient could be obtained. The resulting organization, named the Southeastern Organ Procurement Foundation (SEOPF), shared kidneys among nine institutions based on computer-assisted matching of all potential recipients in that region. The SEOPF network expanded to include 46 transplanting institutions and led in 1984 to the incorporation of the United Network for Organ Sharing (UNOS) to facilitate organ placement throughout the United States. Similar organ-sharing networks were developed in Europe, Scandinavia, the United Kingdom, and elsewhere. These regional networks began to cooperate in the sharing of human organs and tissues on an international scale.
Converse, J. M., and Casson, P. R.: The historical background of
transplantation. In Rapaport, F.T., and Dausset,
J. (Eds.): Human Transplantation. New York, Grune & Stratton, 1968.
The authors present a history of the principal developments in
transplantation from ancient to modern times, and they include some details
not included in the other histories cited.
Griepp, R. B., and Ergin, M. D.: The history of experimental heart
transplantation. Heart Transplant., 3:145,
1984.
The authors present a brief, interesting, and
well-illustrated summary of the development of heart transplantation.
Hamilton, D.: Kidney transplantation: A history. In Morris, P.J. (Ed.): Kidney Transplantation: Principles and
Practice. London, Grune & Stratton, 1984.
In
this chapter written for the second edition of Kidney Transplantation, the author presents an interesting account of the evolution of
human kidney transplantation from early European experiments to the modern
era.
Moore, F. D.: Give and Take: The Development of Tissue Transplantation.
Philadelphia, W. B. Saunders, 1964.
In this volume
is presented a concise review of developments in basic biology and in medicine
and surgery that apply to therapeutic renal transplantation. Interesting
aspects of historic renal transplants in Boston are described by the author,
who was there at the time and has communicated personally with scientists
there and elsewhere who have made notable contributions. For the student,
this book is an informative introduction to the subject of transplantation,
and for the lay reader it is a readily understood account of some interesting
developments in biology and medicine.
Starzl, T. E., Iwatsuki, S., Van Thiel, D. H., Garmer, J. C., Zitelli,
B. J., Malatack, J. J., Schade, R. R., Shaw, B. W., Jr., Hakala, T. R., Rosenthal,
J. T., and Porter, K. A.: Evolution of liver transplantation. Hepatology,
2:614, 1982.
The
researcher, physician, and author who has contributed the most to the development
of liver transplantation provides an authoritative account of the development
of the field.
Terasaki, P. I. (Ed.): History of Transplantation: Thirty-five
Recollections. Los Angeles, UCLA Tissue Typing Laboratory, 1991.
Personal reminiscences of pioneers who were involved in the initiation
of clinical transplantation in the 1950s and 1960s are presented in unedited
form.
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