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Historical Overview of Transplantation

Clyde F. Barker1,2 and James F. Markmann2

1Department of Surgery, Hospital of the University of , Philadelphia, Pennsylvania 19104 2Department of Surgery, Harvard Medical School, and Division of Transplantation, Massachusetts General Hospital, Boston, Massachusetts 02114 Correspondence: [email protected]

Except for legends and claims of miracles, most histories of transplantation cover only the last 60 years because there were no earlier successes. However, the story of even this era has been documented in such rich detail that a full account would fill several volumes. Thus, this brief summary must be limited to highly selected “landmarks.” Some landmarks had an immedi- ate impact, but the importance of others went unrecognized for decades. Some findings that deserved landmark status were overlooked or forgotten, whereas others of no biological significance had major impact. Placing these events in perspective is challenging. Several of transplantation’s pioneers are still alive, and most of the others are within living memory. Virtually all of them have produced their own accounts. For the most part, they agree on what the “landmarks” are, but their differences in emphasis and perspective make an inter- esting story.

PRE-HISTORY: THE ERA OF MYTHS twentieth century was it ever mentioned that AND MIRACLES grafts might fail. Even the great eighteenth cen- he idea of replacing diseased or damaged tury experimentalist John Hunter, who trans- Tbody parts has been around for millennia. planted human teeth and autotransplanted Envisioned were complex transplants such as cocks’ spurs into their combs, seemed unaware the “successful” transplantation of an entire leg that homografts would fail (Martin 1970). Only by the 3rd century sainted physicians Cosmos in the last half of the 20th century has there been

www.perspectivesinmedicine.org and Damien, which is depicted in several fa- a consensus that the outcome of homografts dif- mous paintings (Zimmerman 1998). As early fers from that of autografts. as 600 B.C., the use of autogenous skin flaps to For a long time, proponents of skin homo- replace missing noses was conceived, and by the grafts refused to admit that they wouldnot work. sixteenth century, Gaspare Tagliacozzi (Taglia- Success was even claimed for grafts of whole ears cozzi 1597) and other pioneering plastic sur- and noses. After centuries of sloppy observation geons were successful with such procedures. and self-deception, the realization crept in that The obvious extension of these methods was to detached (free) skin grafts were useless. In ret- use detached or “free” grafts of the patient’s own rospect, the technical failure of even the early tissue or that of other donors. But not until the autografts was not surprising because at first

Editors: Laurence A. Turka and Kathryn J. Wood Additional Perspectives on Transplantation available at www.perspectivesinmedicine.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a014977 Cite this article as Cold Spring Harb Perspect Med 2013;3:a014977

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C.F. Barker and J.F. Markmann

full-thickness skin grafts were used. These thick (the accepted hallmark of immunity) could be grafts never became established because their detected. underlying layer of fat and other tissue prevent- Georg Scho¨ne may deserve recognition as ed revascularization. The first major technical the first transplantation immunologist. Work- advance (almost a “landmark”) came only in ing in Ehrlich’s laboratory in 1912, he studied 1869, when Jacques-Louis Reverdin discovered grafts of skin rather than tumors. Hedetermined that small, thin (split thickness) grafts would that homografts always failed and that subse- heal (Reverdin 1869). His autogenous “pinch quent grafts from the same donor failed more grafts” successfully covered burns, ulcers, or rapidly than the first (Scho¨ne 1912). Three de- open wounds. Others caught on, and soon an cades later, several would be squab- extensive experience with both autografts and bling for the credit of discovering this “second homografts was accumulated. Surprisingly, nei- set” response, suggesting that they deserved a ther Reverdin nor other enthusiasts (including share of Medawar’s , which in part well-respected surgeons such as Joseph Lister) was based on this landmark observation. noticed that homografts were inferior to auto- By the end of the 1920s, scientists at the grafts (Goldman 1987). Only one report of the Rockefeller Institute firmly established other time suggested otherwise. In 1871, the British tenets of transplantation includ- George Pollock described a set of suc- ing the central role of the lymphocyte. James cessful autogenous grafts, while on the same pa- B. Murphy’s work was especially prescient tient’s wound, homografts both from himself (Murphy 1914a; Silverstein 2001). He showed and another donor soon “disappeared” (Pollock that resistance to tumor homografts was depen- 1871). This report was ignored while for addi- dent on the lymphoid system. He sought to ex- tional decades claims of successful homografts tend survival by getting rid of lymphocytes continued. In one such case during the Boer with irradiation, splenectomy, or benzol, the War, Winston Churchill donated skin to help first chemical immunosuppressive agent, noting heal the open wound of a fellow officer. Years that these methods decreased the lymphocytic later, Churchill (1944) reported that this graft infiltration he observed in failing homografts was still successful. (Murphy 1914b). Murphy was convinced that these cells were responsible for homograft de- struction. He could not explain how, because TRANSPLANTATION RESEARCH OF of the firmly prevailing notion of the time that A LOST ERA lymphocytes were fixed cells that lacked mobil- Although consensus on the fate of homografts ity. All of these findings were published in widely www.perspectivesinmedicine.org would not be reached for another 50 years, dur- read scientific journals, but they were ignored by ing the first decades of the twentieth century most and eventually were largely forgotten. Da- several well-known investigators established vid Hamilton in his excellent recent history dubs not only the inevitability of homograft failure this the “lost era” of transplantation (Hamilton but most of the other basic principles of trans- 2012, pp. 105–125). plantation immunology. In 1903, studied transplantation of tumors in mice with- PIONEERS OF ORGAN GRAFTING out bothering to determine the response to transplants of normal tissue (Medawar 1958). Half a century before proponents of skin homo- The use of tumor homografts confused the issue grafts finally conceded their futility, surgeons because they would sometimes overwhelm their using the more complex model of kidney trans- recipients before being rejected. Inthe sameyear, plantation recognized that homograft failure the Danish Carl Jensen (1903) per- was inevitable. is commonly cred- ceived that the failure of tumor homografts ited with originating both vascular suturing and was an immune reaction, but this explanation its use in (Fig. 1). Al- was discounted by Ehrlich because no antibody though the award of the 1912 Nobel Prize for

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Historical Overview

moved to , where he partnered with the physiologist Charles Guthrie. They collaborated for barely 12 months, but during this time, they successfully transplanted the kidney, thyroid, ovary, heart, lung, and small bowel, averaging a publication on this workevery 14 days (Malanin 1979). Carrel’s success with organ grafts was not dependent on a new method of suturing but on his use of fine needles and suture material, his exceptional technical skill, and his obsession with strict asepsis. Carrel’s relationship with Guthrie soon cooled because Guthrie objected to Carrel’s sev- en single-author papers about their joint work and to Carrel’s habit of advancing his fame by reports in the newspapers. After Carrel left Chi- Figure 1. Alexis Carrel, whose pioneering work on cago in 1906 for the Rockefeller Institute in blood vessel suturing and organ transplantation was New York, Guthrie published in Science a criti- recognized by the 1912 Nobel Prize. (Photograph ca. cism of Carrel and the contention that he, rather 1907 from the collection of the American Surgical than Carrel, deserved most of the credit for their Association.) joint accomplishments. He wrote: “It is a singu- lar fact that up until the time Carrel and I en- his development of these techniques was well gaged in the work together, his experiments did deserved, he was actually not the first in either not yield good results, and that our results al- endeavor. Mathieu Jaboulay, the Chief of Sur- most from the beginning of our work together gery in Lyon, where Carrel trained, and the Ger- were excellent!” (Guthrie 1909). This was only man surgeon Julius Do¨rfler introduced the one of several instances in which the Nobel Prize full-thickness blood vessel suturing technique Committee saw it differently than some of the (Do¨rfler 1895; Jaboulay and Brain 1896). Carrel candidates, and Guthrie was not given a share of only adopted this method a decade later on the the Nobel Prize. advice of Charles Guthrie after he initially ad- Carrel’s extensive experience with organ vocated partial thickness suturing. transplants in animals left no doubt that, al- Technically successful kidney transplants though autografts could be consistently success- www.perspectivesinmedicine.org were accomplished first not by Carrel but by ful, homografts never were. In view of the stub- Emerich Ullmann, who in 1902 performed a born ongoing claims of successful skin homo- dog autotransplant and a dog-to-goat xenograft grafts, this was one of Carrel’s most important (Ullmann 1914). In 1906, the first two renal findings, in itself a landmark. Carrel did not transplants in humans were performed by Ja- know why homografts failed, but he began to boulay using a pig donor for one and a goat explore methods to avoid this such as matching donor for the other (Jaboulay 1906). Ernst Un- of donor and recipient. Under the influence of ger, after first performing more than 100 kidney his colleague James B. Murphy, he irradiated re- transplants in animals, performed the third and cipients in unpublished and now forgotten ex- fourth human transplants in 1909 using monkey periments, finding that this improved results donors (Unger 1910). None of these early hu- (Flexner 1914). man kidney xenografts functioned for more interrupted the productive than a few days, and all of the patients soon died. transplantation research at the Rockefeller Insti- In 1904, Carrel left after failing in tute by Carrel, Murphy, and their colleagues. several examinations to qualify for a faculty po- Carrel, after spending the war in France treating sition there. After a brief sojourn in Montreal, he wounded soldiers, returned to the Rockefeller

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C.F. Barker and J.F. Markmann

Institute but not to research in transplantation. rats was governed by the extent of genetic dis- Instead, he formed an unlikely partnership with parity of donor and recipient. He also showed the aviator , who approached that the lymphocyte was involved (Loeb 1945). him to discuss the possibility of a heart opera- As Chief of Pathology, he influenced his plastic tion on a relative. Carrel responded that open surgeon colleagues James B. Brown and Earl heart surgery would require a pump oxygena- Padgett in studies determining that identical tor. Lindbergh offered to build such a device, twins would accept exchanged skin grafts and Carrel provided laboratory space for the (Brown 1937). Loeb reported his finding that project (Lindbergh 1978). Lindbergh’s pump grafts exchanged between (inadequately) inbred was not used for heart surgery but for perfusion mice of the same strain would fail, mistakenly of organs and tissues. It allowed preservation of claiming that this was due to some mystical organs for as long as 3 weeks (Anonymous “finer mechanism.” For this error (later retract- 1931). The publicity-seeking Carrel made sure ed after further inbreeding of his mice), he was that the pump was prominently exhibited at the viciously ridiculed by his famous faculty col- 1939 New York World’s Fair. league, the geneticist C.C. Little, and by others Carrel was the originator of tissue culture, including , whose unfair antip- another technique that subsequently played an athy for Loeb influenced him to dismiss the important role in transplantation. He incubated importance of the lymphocyte and for years small fragments of embryonic chicken heart in espouse the humoral theory of rejection (Ha- dilute plasma. Carrel claimed that by 1919, this milton 2012, p. 160). This dispute forever tar- “immortal” tissue had been cultured for 1939 nished the reputation of Leo Loeb, a forgotten passages and was still normal and pulsating. But hero of transplantation research. it was subsequently determined that embryonic cells with a normal diploid set of chromosomes UNMODIFIED ANIMAL AND cannot be maintained in culture for more than HUMAN KIDNEY TRANSPLANTS 50 doublings unless they undergo malignant transformation. Carrel’s laboratory technician In 1933, the Soviet surgeon Yu Yu Voronoy per- eventually admitted the fraud, saying that be- formed the first human-to-human kidney trans- cause Dr. Carrel would be upset if the strain was plant. That the kidney was not procured until lost, she added new cells when they were 6 hours after the donor’s death and that it was needed (Witkowski 1980). transplanted across a major blood group mis- Despite the continued claims of success for match probably accounted for its prompt failure skin homografts, the well-documented failure (Voronoy 1937). Four other human homografts www.perspectivesinmedicine.org of experimental organ homografts by Carrel that Voronoy performed between 1933 and 1949 discouraged further research in this field, which also failed rapidly. Published in Russian, this during the 1920s and 1930s was continued by experience remained unknown in the West until only a few. Frank Mann at the Mayo Clinic con- the 1950s. ducted extensive studies of canine renal and In the 1940s and early 1950s, experimental heart homografts but failed to extend Carrel’s dog was actively con- earlier findings or explore Carrel’s suggestions ducted by surgeons in Paris and Boston and for preventing rejection (Mann 1932). also by Morton Simonsen in Denmark and Wil- liam Dempster in London. The “second set” phenomenon was again observed, but no new LEO LOEB, A FORGOTTEN HERO insights emerged. Simonsen searched in vain In the 1930s, Leo Loeb, an e´migre´ from Nazi for an antibody response, being unaware of Germany working at Washington University in Loeb’s work on the lymphocyte (Simonsen St. Louis, was one of only a few transplantation 1953). Dempster, who joined Medawar in de- researchers. He determined that the strength nouncing Loeb and his cellular theory of immu- and timing of rejection of skin homografts in nity, may have been the first to use radiation in

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Historical Overview

organ transplant recipients (Dempster 1953a). others, this kidney promptly functioned, but it He also treated dog homograft recipients with was rejected after 3 weeks. cortisone (Dempster 1953b), which Rupert Bil- In the concurrent Boston program at the lingham had found to prolong survival of skin Peter Bent Brigham Hospital, David Hume per- homografts in rodents (Billingham and Krohn formed nine kidney transplants between 1951 1951). In dogs, neither treatment had much ef- and 1953 (Hume et al. 1955). The donors were fect on rejection. Dempster like others despaired patients who had died during surgery or hydro- of further progress in organ transplants and ad- cephalus patients who had a normal kidney re- vised against any attempt in humans. moved so that its ureter could be used as a con- The faint hope that homografts might fare duit to drain their excess cerebrospinal fluid to better in humans than animals was spectacularly the bladder. Except for one orthotopic trans- rekindled in 1950 when Chicago urologist Rich- plant, they were placed in the anterior thigh ard Lawler performed a human kidney trans- with the ureter brought out to the skin. Some plant (Lawler et al. 1950). In this patient whose of these recipients were treated with ACTH, renal function was impaired but not terminal, cortisone, and testosterone. Only four kidneys the homograft was claimed to be successful. It showed any function, and in three of these, func- may have producedurine briefly,but when it was tion was brief. But, remarkably, one transplant removed after several months, it was found to be functioned for 5.5 months before it was rejected. shrunken. This procedure was of no scientific This helped sustain the hope that in humans the significance and of no benefit to the patient, outcome of homografts might be better than who survived for several years with declining predicted from animaltransplants, thus possibly renal function of her own kidney. Within the justifying continued attempts made in as many medical profession, this “maverick attempt” assixmorepatientsthatwereneverreported.But was widely criticized, and Lawler’s urology in the opinion of most physicians of the time, the colleagues treated him with distain. However, Paris and Boston experience confirmed the futil- because enthusiastic reports in the lay media ity of kidney homografts, proving that such hu- generated public support, the impact of this man experimentation was unwarranted and un- transplantwassubstantially positive.TheFrench ethical. However, two landmark events would surgeon Rene´ Ku¨ss said that it provided him the soon conspire to brush aside this pessimism excusetostart aprogramin humankidney trans- and launch the modern era of transplantation. plantation (Ku¨ss 1991). Because no method was available to prevent PRELUDE TO THE MODERN ERA rejection, it was recognized that the chances of www.perspectivesinmedicine.org success were remote, but the lack of dialysis or The prelude to the modern era of transplanta- any other treatment for renal failure was used tion began by chance. During World War II, to justify trials of transplantation in otherwise Peter Medawar, a young Oxford zoologist who doomed patients. In 1951, two teams working had no previous interest in transplantation, was separately in Paris performed nine kidney trans- assigned to join plastic surgeon Thomas Gibson plants (Ku¨ss and Bomget 1992). Most of the in exploring the use of skin homografts for donors were guillotined criminals. The kidneys treatment of burned aviators (Gibson and Med- were placed retroperitoneally in the pelvis revas- awar 1943). Working in the Burn Unit of Glas- cularized by iliac vessels with the ureter anasta- gow’s Royal Infirmary, they soon reconfirmed mosed to the bladder, a method devised by that homografts always failed. Medawar attrib- Ku¨ss that is still the standard operation. None uted to Gibson the credit for their rediscovery of of these transplants showed meaningful func- the “second set phenomenon” previously de- tion, and all of the patients died within days scribed in animals by several others including or weeks (Ku¨ss et al. 1951). The ninth transplant Scho¨ne in 1912 and in a human patient by Emile in this series was the first to use a living relative Holman in 1921 (Scho¨ne 1912; Holman 1924). as the donor, the patient’s mother. Unlike the Like the earlier researchers, they realized that

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C.F. Barker and J.F. Markmann

this identified rejection as an immunological Medawar had little scientific interest in the out- event. This important observation and its inter- come of the skin grafts, which they felt was en- pretation are often credited to Medawar as tirely predictable. However, the results were un- an original discovery and a novel insight. They expectedly interesting(Billingham1991)(Fig.2). were not, but Medawar’s many subsequent con- They found that most cows accepted their tributions were so important, his experiments twin’s graft, a surprising result because they so precise, and his speaking and writing so mas- knew that most cattle twins are fraternal and terful that he rightfully deserved to be consid- some of the twin pairs they grafted were of dif- ered the central figure in the emerging field of ferent genders (Anderson et al. 1951). Totally transplantation. puzzled by this finding, they discussed it with Returning to Oxford after the war, Medawar Hugh Donald, who suggested that they read a conducted extensive studies of skin homografts paper published 4 years earlier in Science. When in rabbits, more firmly characterizing the tim- they did so, the significance of their results sud- ing, histological morphology, and immunolog- denly became clear. ical nature of rejection (Medawar 1944). Partly Toplace the cattle twin chapterof the storyof because Medawar was unaware of James B. Mur- tolerance in proper context, it is necessary to go phy’s work on the lymphoid system 20 years ear- back 200 years. In 1779, the English surgeon lier and refused to believe Leo Loeb’s similar John Hunter provided the first anatomical de- findings of the 1930s, he remained convinced scription of the freemartin, a term used for the for another decade that grafts failed because of generally sterile female of a pair of cattle twins humoral rather than cellular immunity (Brent of unlike sex. Hunter dissected freemartins, 1997). Frustrated that no antibody could be finding that they had masculinized sex organs detected, Medawar then turned his attention (Palmer 1835). That Hunter was unable to ex- away from . Instead, he and plain this curious phenomenon is ironic because his first graduate student, Rupert Billingham, he was an authority on the circulation of the began to study the esoteric phenomenon that, placenta. in spotted guinea pigs, the pigmented areas of skin autografts gradually encroach on the sur- rounding white skin (Billingham and Medawar 1948). Soon after this, Medawar accepted the Chair of Zoology at the University of Birmingham, recruiting Billingham to join his faculty. To- www.perspectivesinmedicine.org gether they continued to study pigment spread. In 1949, serendipity assumed importance in the story. At a cocktail party Medawar talked with his faculty colleague Hugh Donald, who was studying twin cattle. Donald asked whether identical twins could be distinguished from fraternal twins. Medawar responded that skin grafts exchanged between twins would be ac- cepted only by the identical ones. When Donald requested that he perform such experiments, Medawar was reluctant because he was uncomfortable with Figure 2. Peter Medawar skin-grafting a cow. The unexpected acceptance of grafts exchanged between the prospect of handling large animals. There- chimeric bovine fraternal twins was the key to under- fore, he enlisted the aid of his junior colleague, standing tolerance. (The photograph is a gift from the Billingham, who as the grandson of a dairy far- private collection of Rupert Billingham, who was the mer was not afraid of cows. Billingham and photographer.)

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Historical Overview

The next important link in the story was derstood why cattle accepted their fraternal provided in 1916 when Frank Lillie, an embry- twin’s graft. They realized that, like the freemar- ologist at the , dissected tins studied by Hunter, Lillie, and Owen before a pair of unborn cattle twins (Lillie 1916). He them, their twins must have exchanged blood in found that the chorions of the twins’ placentas utero and that the donor cell chimerism persist- were fused, causing a common intrauterine cir- ed in adulthood. They reasoned that the stem culation that would allow blood to be exchanged cells exchanged in utero by these twins would freely between the twins. Like John Hunter, Lillie be not only those for red blood cells but also also found that when cattle twins were of unlike for leukocytes, and that these were probably re- sex, the gonads of the female were usually rudi- sponsible for skin graft acceptance. They also mentary. He reasoned that male hormones cir- realized at once with considerable excitement culating through the female embryo inhibited that it might be easy for them to repeat Nature’s the development of its reproductive organs. bovine twin experiment in other species. In Three decades later, in 1945, Ray Owen at 1951, Billingham and Medawar moved to Uni- the University of Wisconsin wrote the next versity College, London. Medawar said, “Thank chapter. In studying erythrocytes in cattle, God we’ve left those cows behind.” Owen found that in this species fraternal twins In London, Billingham, Medawar, and grad- frequently had a mixture of two red blood cell uate student Leslie Brent set out to induce chi- types (Owen 1945). Recalling Lillie’s finding of merism and homograft acceptance in mice placental fusion of bovine twin , Owen by inoculating intrauterine fetuses with donor concluded that not only hormones but also cel- strain spleen cells (Fig. 3). In retrospect, they lular elements of the blood must be exchanged were quite lucky to have achieved any successes. in utero by twin cattle. He realized that persis- By chance, the inbred strains they chose for the tence of red blood cell chimerism in adulthood experiments were CBA and A, virtually the only must depend on intrauterine transfer not only H-2-incompatible combination available to of short-lived red blood cells but also of stem them in which neither graft-versus-host disease cells that would perpetuate them. nor incompatibility of skin-specific antigens Six years after the publication of Owen’s would cause death or rejection of the graft. largely forgotten paper, Billingham and Meda- In adulthood, survivors of their intrauterine war read it with fascination and suddenly un- inocula accepted skin grafts but only from the www.perspectivesinmedicine.org

Figure 3. Rupert Billingham and Leslie Brent in their laboratory, where they inoculated neonatal mice with spleen cells (upper insert). In adulthood, the mice accepted skin homografts from the donor strain (lower insert). (The photographs are a gift from Rupert Billingham’s private collection.)

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spleen cell donor strain (Billingham et al. 1953). mark. On December 23, 1954, Like the cattle work, it showed that allograft bypassed the barrier of rejection by using the rejection was not inevitable. Surprisingly, nei- patient’s identical twin as the donor of a human ther the publication of the work in October kidney transplant (Fig. 4) (Murray et al. 1955; 1953 nor its presentation at a New York Trans- Merrill et al. 1956). In retrospect, the success of plantation meeting the next year had sudden this transplant had no real scientific significance dramatic impact, in part because of Medawar’s because technical accomplishment of human statement that it had no clinical implication kidney transplants was nothing new and it had (Hamilton 2012, pp. 225–226). Over time, also been known for decades that skin grafts however, it is clear that no other experiment in exchanged between identical twins were not re- the field has approached the importance of their jected (Brown 1937). But, the impact of this first demonstration that induction of chimerism can successful human transplant was immediate prevent graft rejection. It resulted in Medawar’s and profound. Widespread enthusiastic reports 1966 Nobel Prize, and it reverberates in present- were an important stimulus for surgeons to day clinical trials to induce tolerance. pursue further efforts in transplantation. But During their experiments to induce toler- because induction of chimerism in human re- ance, Billingham and Brent made another quite cipients by neonatal treatment was clearly im- unexpected observation. Many of their chimeric possible, another approach would be necessary. mice were sickly “runts.” They soon determined The next year, one was found by Joan Main and that this was because immunocompetent cells in Richmond Prehn, who showed that weakening the neonatal inocula migrated to and attacked the immune system of adult mice by radiation the lymphoid tissues of their new hosts—that allowed them to induce chimerism by inoculat- is, graft-versus-host disease (GVHD). Although ing bone marrow cells. Skin grafts were then they briefly reported this in 1957, publication accepted if they came from the bone marrow of their conclusive proof was delayed until 1959 donor strain (Main and Prehn 1955). This and by Brent’s extended sabbatical with Ray Owen the similar success of the method in one dog (Brent 1991). Meanwhile, in 1957, Morton Si- kidney homograft (Mannick et al. 1959) en- monsen had independently discovered and pub- couraged transplantation teams in Paris and lished his evidence for GVHD in chickens that Boston to pursue this approach for preventing he had injected as embryos with allogeneic rejection of human kidney homografts. lymphoid cells (Simonsen 1957, 1985). That to In 1958, Murray’s team used the Main– cause GVHD, lymphocytes must be mobile was Prehn strategy in two human kidney recipients among the findings belatedly inducing Meda- that they conditioned with lethal total body ir- www.perspectivesinmedicine.org war to accept the importance of cellular immu- radiation (TBI) and donor bone marrow. Ten nity, of which he became the foremost propo- other patients were treated with sublethal TBI nent. Even better evidence of cellular immunity without bone marrow. Disappointingly, 11 of was provided by Avrion Mitchison’s demonstra- the 12 irradiated patients died within a month tion that immunity to tumor grafts could be (Murray et al. 1962). The survivor (who was not transferred by cells but not antibody (Mitchison given bone marrow) maintained adequate func- 1954). Final proof of lymphocyte mobility came tion of his fraternal twin brother’s kidney for 20 in 1959 when James Gowans (Gowans 1957) years. Scientifically, this was a more important showed that lymphocytes recirculate from blood accomplishment than the identical twin case to lymph and back again. because it was the first time the genetic barrier to human kidney transplantation had been breached (Merrill et al. 1960). Five months later THE FIRST SUCCESSES in Paris, Jean Hamburger and colleagues (Ham- In Boston, barely 14 months after the initial burger et al. 1959) using the same irradiation report of tolerance in chimeric mice by Billing- treatment were successful with another fratern- ham, Brent, and Medawar, came the next land- al twin transplant, which functioned until the

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Historical Overview

Figure 4. Joseph Murray and his team performing the first successful kidney transplant in 1954 using as a donor the recipient’s identical twin.

patient’s death from unrelated causes 26 years for radiation. In the 1950s, oncologists were later. evaluating drugs including nitrogen mustard In these two dizygotic twin cases, there was and 6-MP for treatment of malignancies. In speculation that the donor and recipient, like 1959, interest was drawn to the use of such drugs twin cattle, had become chimeric by exchang- for transplantation by the report of an experi- ing tolerogenic blood cells during gestation. ment by Robert Schwartz and William Dame- However, between 1960 and 1962 in Paris, Jean shek at Tufts University. They found in rabbits Hamburger and Rene´ Ku¨ss showed that this that 6-MP reduced the antibody response to bo- was unnecessary by performing four successful vine albumen (Schwartz and Dameshek 1959). transplants in nontwin recipients conditioned In 1960, they reported that the drug modest- www.perspectivesinmedicine.org by (Ku¨ss 1962). This ly extended the survival of skin homografts French experience was the principal (and per- (Schwartz and Dameshek 1960). When Roy haps the only) justification for continuing hu- Calne, a surgical trainee in London, learned of man kidney transplantation. Because bone mar- these experiments, he tested the effect of 6-MP row inocula were not used in these patients, it on rejection of dog kidney homografts and was assumed that chimerism was not necessary found that it significantly prolonged their sur- for success. vival. He promptly reported this in Lancet (Calne 1960). Simultaneously, Charles Zukoski working in Richmond with David Hume in- CHEMICAL dependently made the same observation, but Although Hamburger and Ku¨ss both used adre- his report in the Surgical Forum did not appear nal cortical steroids as an adjunct to TBI and until the following year (Zukoski et al. 1960). Ku¨ss secondarily administered 6-mercaptopu- Calne also treated three human kidney recipi- rine (6-MP) to one of his irradiated patients, ents with 6-MP,but they all died without show- there was as yet no systematic investigation of ing any function of the transplant (Hopewell drug-based immunosuppression as a substitute et al. 1964).

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C.F. Barker and J.F. Markmann

In 1960, with Medawar’s help, Calne ob- the conference as an afterthought. He described tained a research fellowship with Joseph Murray a new immunosuppressive protocol that had al- in Boston. Although Murrayadvised him to pur- lowed .70% 1-year renal graft survival. He had sue the Brigham’s ongoing experiments with more surviving patients than the rest of the whole body irradiation, Calne began working world’s better known participants combined. instead with 6-MP and its derivative azathio- At first, his audience was incredulous. Tapes prine, which he obtained from Gertrude Elion that recorded the subsequent sometimes acri- and George Hitchings (Hitchings and Elion monious discussions were lost, but eventually 1954), who were subsequently awarded the No- Starzl’s unprecedented results had to be believed bel Prize for development of these immunosup- because he had brought with him charts detail- pressive agents. Calne’s demonstration that in ing the daily progressof each patient—including dogs kidney transplant rejection could some- laboratory tests, urine output, and immunosup- times be delayed substantially with these drugs pressive drug doses (Hamilton 2012, pp. 279– stimulated the Brigham team to begin using 280, 487). Starzl’s innovation based on his con- them in human kidney recipients. sistent success in reversing homograft rejection in dogs was to add prednisone to azathioprine. Although rejection usually occurred in patients NATIONAL RESEARCH COUNCIL on azathioprine alone, it was usually reversible CONFERENCE with large doses of prednisone. In most patients, In 1963, one of the most important landmarks drug doses could then be diminished without in the history of transplantation was revealed provoking rejection. This presentation caused during a small conference organized by the Na- a sensation (Ku¨ss 1992). The formal report of tional Research Council (NRC). About 25 indi- the conference consolidated the results of all viduals including most of the world’s active participants. This failed to stress and seemed transplant clinicians and scientists assembled almost to obfuscate the dramatic reaction to in Washington to review the status of human Starzl’s presentation. In fact, the impact on those kidney transplantation. The results presented present was extraordinary. They would have by these acknowledged experts were extremely been still more impressed if they could have discouraging. Less than 10% of their several known that half a century later, some of the pa- hundred allograft recipients had survived as tients Starzl described would be off immuno- long as 3 months (Goodwin and Martin 1963). suppression with the same functioning allo- Of patients treated with total body irradiation, grafts and that they would have been found only six had approached or achieved 1 year sur- microchimeric with their donors’ lymphoid www.perspectivesinmedicine.org vival (Starzl 2000). Hope was expressed that cells. immunosuppressive drugs might be more ef- The outlook for renal transplantation was fective. Murray reported his first 10 patients completely changed by Starzl’s report. Trans- treated with 6-MP and azathioprine instead plant historian Nick Tilney described it as “let- of irradiation (Murray et al. 1963). One had ting the genie out of the bottle” (Tilney 2003). survived for a year, although at the time of Many of the conference attendees promptly vis- the conference it was failing. The others died ited Starzl in Denver to learn how to adopt his within 6 months. Thus, at this point, drugs immunosuppressive protocol (Starzl 1990). The seemed no more effective than radiation. The news of the breakthrough spread quickly by its mood at the conference was so gloomy that publication 5 weeks later (Starzl et al. 1963). Be- some participants questioned whether contin- fore the NRC conference, there had been only ued activity in human transplantation could be three active renal transplant centers in North justified (Ku¨ss 1992). America (Boston, Denver, and Richmond). As The gloom was dispelled byonlyone presen- the effectiveness of Starzl’s innovative immuno- tation given by Tom Starzl, a virtually unknown suppression became known, within a year 50 newcomer to the field, who was invited to new transplant programs began in the United

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Historical Overview

States alone. All of them and others that began only after Congress in 1972 approved Medicare subsequently adopted the Starzl “cocktail im- funding for patients of any age with end-stage munosuppression.” In fact, this protocol re- renal disease. mained the virtual world standard for almost the next two decades (Brent 1997). Brain Death Before the mid 1960s, utilization of kidneys A PERIOD OF CONSOLIDATION from deceased donors was limited by the ische- The next quarter century, 1964–1980, is often mic damage that set in as soon as the heart classified as a period of consolidation or plateau. stopped beating, this being the time-honored During this period, except for the development definition of death. During the next few years, of antilymphocytic serum (in large part respon- there was gradual although controversial accep- sible for the first albeit marginal success of ex- tance that irreversible loss of brain function was trarenal transplants), there were no landmarks. also a form of death and one that would allow Importantly, however, there was steady progress. removal of organs from a “heart-beating cadav- Practical innovations and accomplishments er.” In 1968, the “Harvard ad hoc Committee on took place that were necessary for maturation Brain Death” published its recommendation of kidney transplantation into a useful clinical that irreversible loss of brain function be accept- service. These included availability of dialysis; ed as death (Harvard Medical School 1968). Medicare funding of end-stage renal disease; an- Uneasiness that this might be influenced by tibody screening to avoid hyperacute rejection; the desire of transplanters to recover organs the importance of tissue typing for related do- from possibly salvageable patients and criticism nor transplants; acceptance of brain death; ex over the poor outcomes of the first heart trans- vivo preservation, allowing donor organs to be plants that were being performed during this transported and shared;, and, perhaps most im- same period fueled controversy over this con- portantly, the accumulation of experience in pa- cept. But eventually, brain death was widely ac- tient management that led to the avoidance of cepted, a crucial factor in increasing numbers of over-immunosuppression, thereby decreasing transplants, especially of extra renal organs. resultant infections and deaths. Organ Preservation Hemolysis As early as 1905, Carrel’s colleague Charles Hemodialysis for renal failure was pioneered in Guthrie had advocated cooling to protect donor www.perspectivesinmedicine.org Holland by Willem Kolff during World War II, organs before transplantation (Hamilton 2012, but chronic renal failure could be treated only p. 101). That it was not used in early human after Belding Scribner in 1960 devised Teflon transplants probably in part accounted for their arteriovenous conduits for long-term vascular poor results. Initially, Starzl used total body access (Kapoian 1997). Before that, each dialysis hypothermia to protect donor organs, but by treatment used up an accessible artery and vein 1960 switched to infusing cold solution into until they ran out. In 1966, James Cimino and the portal vein to protect donor (Mar- Michael Brescia introduced subcutaneous anas- chioro et al. 1963). By 1963, pretransplant in- tamoses of an artery and vein at the wrist to fusion of cold solution into the renal artery arterialize superficial arm veins that could of donor kidneys became standard (Collins then be accessed by simple needle puncture. 1969). When multiple organs were procured But even in the late 1960s, chronic dialysis was from a donor, in situ cooling by infusion of available in only a few centers, and in these ex- cold solution to the aorta was used. Ex vivo per- pense limited its use to a small number of pa- fusion of isolated kidneys by a pump (reminis- tients. Proliferation of centers able to offer cent of Lindberg’s machine in the 1930s) was chronic dialysis and transplantation took place shown to extend preservation of kidneys for

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C.F. Barker and J.F. Markmann

2–3 days (Belzer et al. 1967), but the popularity human leukocyte antigen (HLA) (Snell 1948; of this method waned after 1987 when Folkert Dausset 1958). Antibodies against this antigen Belzer introduced University of Wisconsin sol- were identified in transfused patients and mul- ution, which when simply infused into blood tiparous women by Rose Payne (1957) and Jon vessels of donor organs allowed preservation al- van Rood (van Rood et al. 1958) soon after. Test- most as long (Belzer et al. 1992). ing for antibodies (by agglutination techniques) was cumbersome and inconsistent until Paul Terasaki in 1964 developed a microcytotoxicity Donor Organ Sharing assay (Terasaki 1964). His test, which mixed re- Afterdonor kidney preservation of upto6 hours cipient serum and donor lymphocytes in tiny was accomplished in the mid-1960s, sharing of wells, quickly became the standard. For several organs between centers became practical. At years,Terasakidid the typingformostU.S. trans- first, sharing was local and informal. In 1967, plant centers. Several of his early findings were of Paul Terasaki started the first sharing organiza- lasting importance (Terasaki 1990): (1) a posi- tion in Los Angeles (Terasaki 1990). The Boston tive cross-match test identifying donor-specific InterhospitalOrganBankfollowedin 1968.Sub- antibodies in the serum of a prospective kidney sequently, perceptions arose that local control recipient predicts hyperacute rejection; and (2) allowed inequity of donor organ allocation. matching can reliably identify the optimal do- There was concern that U.S. organs were sent nor within a family. It was next assumed by his- abroad or transplanted at U.S. centers into for- tocompatibility experts that matching would be eign nationals. Recognition of a need to formal- just as important in selection of unrelated do- ize distribution of donor organs at a national nors. However, in 1970, when Terasaki examined level led Congress to pass the National Trans- his large database (1216 kidney transplant pa- plant Act in 1984. The Southeastern Organ tients from 52 centers) to relate typing with out- Procurement Foundation (SEOPF), founded come of cadaver renal allografts, he found no in 1969 and eventually composed of 12 hospi- correlation. Terasaki’s announcement of this at tals in several cities, served asthe template for the the Transplantation Congress in the Hague elic- resultant national entity that nowcontrols organ ited consternation in members of the tissue typ- allocation and placement, monitors perfor- ing community, who contended that his meth- mance of transplant centers and organ procure- ods must be faulty (Terasaki 1990). His paper ment organizations, collects data, and controls was the only one not accepted for publication quality—the United Network for Organ Sharing in the conference proceedings. NIH made an (UNOS) (McDonald 1988). UNOS has been a emergency site visit to Terasaki’s laboratory www.perspectivesinmedicine.org force for order and good, but to some its effec- and abruptly withdrew his grant, closing down tiveness has seemed compromised by the exces- most of his research. His funding was subse- sive scale of its tasks and the number and size of quently restored when others confirmed that its committees and inevitable bureaucracy. Ad- his findings were correct. Since that time, typing justments in appropriate organ allocation in has improved, with identification of many addi- response to changes in the relative importance tional histocompatibility antigens including of histocompatibility and issues of equity have those of the important Class II locus (D or been difficult, prolonged, and politicized. DR) (Ting and Morris 1978). Histocompatibil- ity matching remains crucial in bone marrow transplantation and important in selection of Histocompatibility Typing family donors. But even now for unrelated do- Although tissue matching was suggested by nororgan transplants, the benefit remains much Alexis Carrel and studied in animals by George less unless there is a perfect match. Snell and by Peter Gorer, it could not begin to Additional important findings that took emerge as a reality for human transplants un- place during the consolidation period are listed til 1958, when discovered the first because space precludes their full discussion:

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Historical Overview

1. Blood transfusions, rather than decreasing by Byron Waksman (Waksman et al. 1961). De- the chance of kidney allograft survival, were pletion of lymphocytes with antiserum was a found during the 1970s to improve it. This logical extension of Gowans’s finding (Gowans still-not-understood observation by Gerhard et al. 1963) that thoracic duct drainage delayed Opelz and others led to protocols of deliberate skin graft rejection in rats. In 1963, Michael pretransplant transfusions (Opelz et al. 1973). Woodruff reported that ALS was remarkably However, this strategy was abandoned when effective in extending skin allograft survival in the even greater improvement due to cyclo- rodent models (Woodruff and Anderson 1963). sporine obscured the benefits of transfusions. Monaco et al. (1966) and Levey and Medawar (1966) reported similar success. In 1966, Starzl 2. In some pigs and rats, homografts sur- was the first to use ALS clinically. After finding vived without immunosuppression and also it effective for kidney allografts, he also credited induced acceptance of other types of graft it with allowing his first successful human liver from the liver donor (Calne 1969; Kamada transplants in 1967 (Starzl et al. 1967a,b). Many 1980). others, including Anthony Monaco, John Na- 3. William Summerlin’s report that pretrans- jarian, and A.G. Sheil, treated patients with plant culture of skin allografts allowed their homemade ALS from rabbits or horses immu- acceptance without immunosuppression nized with lymph node cells or cultured lym- was greeted with excitement but was subse- phoblasts before pharmaceutical companies be- quently proven to be fraudulent. Summerlin gan to produce it. Variability in effectiveness of was painting the grafts to make them look different batches of this polyclonal antiserum viable (Medawar 1996). was troublesome before the advent of mono- clonal derivatives of ALS that were directed first 4. The origin of multiple transplantation soci- at all T lymphocytes and subsequently at their eties, journals, national and international subsets or their interleukin 2 receptors (Cosimi meetings, and registries of clinical results en- et al. 1981). These agents have become a main- sured prompt dissemination of scientific and stay of the modern immunosuppressive arma- clinical findings to a degree not seen in other mentarium, especially for induction therapy. fields.

Cyclosporine and EXTRARENAL ORGAN TRANSPLANTS The next landmark was the “wonder drug” cy- During the period of consolidation, transplan- closporine. After a slow start, it revolutionized www.perspectivesinmedicine.org tation of nonrenal organs (liver, heart, and pan- transplantation by substantially improving kid- creas) began. These landmarks are subjects of ney transplant results and greatly facilitating other articles in this collection. Their ini- successful extrarenal transplants. Cyclosporine tial success (albeit marginal) was promoted by is a fungal derivative first reported in 1976 by improvement in immunosuppression by anti- Jean-Franc¸ois Borel to have immunosuppressive lymphocyte serum (ALS), which thus in itself qualities (Borel et al. 1976). Following several deserves landmark status. Further improvement years of encouraging animal experiments, Calne awaited cyclosporine. began in 1979 to use it as a single agent in treat- ment of human kidney recipients, finding it to be more potent than azathioprine but also toxic ANTILYMPHOCYTE SERUM in higher doses, leading to infections, lympho- Antilymphocyte serum (ALS) had a prolonged mas, and renal failure (Calne et al. 1979). Results evolution. At the end of the nineteenth century, of initial trials in Boston and Canada rated it as Elie Metchnikoff proposed the use of antiserum unimpressive to poor, causing some to believe to mitigate cellular immunity (Metchnikoff the drug should be abandoned. Once again as he 1899), a concept reexplored six decades later had before with azathioprine, Starzl by adding

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prednisone to the new drug developed a proto- 1990, there were only a few trials of this strategy, col that strikingly improved outcomes of kidney the first by Monaco et al. (1976) and the largest transplants (Starzl et al. 1980). In addition, this by W.H.Barber and A.G. Diethelm, who treated transformed transplantation of extrarenal or- 57 kidney recipients with an induction course gans into a practical clinical service (Starzl et of ALG and cryopreserved donor bone marrow al. 1981). given 17 days after transplantation (Barber et al. Cyclosporine soon became the standard 1991). Their results were equivocal, although baseline immunosuppressant and remained so early graft rejection seemed less than in the con- until 1989, when it was shown by Starzl that trol group. rejection of liver and other organ allografts re- In 1992, attention was dramatically refo- sistant to treatment by cyclosporine, steroids, cused on the role of chimerism in human allo- and antibodies could often by reversed by an graft survival. Tom Starzl discovered that donor even more potent drug, tacrolimus (Starzl et al. leukocyte chimerism was present in patients 1989). Tacrolimus has now in large part replaced who had maintained successful kidney or liver cyclosporine as the usual baseline agent. grafts for up to three decades (Starzl et al. 1993). Sensitive immunochemical and molecular as- says were necessary to detect donor cells, which Chimerism in some patients were not found in blood but Modern immunosuppression with agents such only in biopsies of skin, lymph nodes, and other as cyclosporine/tacrolimus and T-cell antibod- tissues. This extensive search determined that a ies nowallows excellent short- and midterm sur- microchemic state was present in all 30 patients vival of allografts, for 1 year exceeding 90% for studied. kidney and approaching this for other organs. Because these recipients had not been given Nevertheless, because of ongoing morbidity donor cells, the chimeric cells could only have from drug toxicity and graft loss from chronic reached them as passengers migrating from the rejection, achievement of drug-free immuno- donor organ. Many of the patients appeared suppression remains the ultimate goal. Plans to be tolerant, because they were off all immu- for inducing tolerance invariably start with re- nosuppression. This finding was the basis of view of the 1953 demonstration by Billingham, Starzl’s belief that chimerism is an important Brent, and Medawar that chimerism induced in cause (not the consequence) of successful trans- neonatal mice by lymphoid cell inocula allows plantation, culminating in his hypothesis of a acceptance of donor strain skin grafts. Main and two-way paradigm for tolerance—that is, suc- Prehn’s subsequent success by infusion of donor cessful engraftment is the result of the responses www.perspectivesinmedicine.org cells to irradiated adult mice inspired pioneer of coexisting donor and recipient cells each to transplanters in Boston and Paris to test this the other causing reciprocal clonal exhaustion method in a small number of human kidney al- followed by peripheral clonal deletion (Starzl lograft recipients, but with no success. When in et al. 1992, 1996). This interpretation has been several irradiated human recipients, graft sur- rebutted by Kathryn Wood, David Sachs, and vival was achieved without donor cell inocula others who argue that persistent microchimer- and in others achieved with immunosuppres- ism induced by a donor organ is as likely to be sive drugs alone, it appeared that donor cell the effect as the cause of tolerance (Wood and chimerism was irrelevant to long-term allograft Sachs 1996). Whatever the resolution of this success. debate, it is clear that Starzl’s demonstration In animal models, there has been continued of microchimerism in his patients has been an exploration of donor cell inocula (combined important stimulus for reexploration of this ap- with immunosuppression) for inducing chi- proach to allograft tolerance by trials described merism and tolerance of allografts (Monaco in Markmann and Kawai 2012). et al. 1966; Lance and Medawar 1969; Thomas The evolution of organ transplantation in et al. 1987). But in humans between 1959 and the last half century is one of Medicine’s great

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Historical Overview

Figure 5. Participants in the March 1999 meeting of the third Annual Longmire Surgical Society Scientific Day Symposium at UCLA: Milestones in Transplantation. This group arrived at a consensus on the Historical Landmarks in Clinical Transplantation. (Front row, left to right) Robert Good, , E. Donnell Thomas, Joseph Murray, Jean Dausset, and Jon Van Rood. (Back row, left to right) Leslie Brent, Roy Calne, Paul Terasaki, Robert Schwartz, Carl Groth, and .

stories. In support of this contention are the five REFERENCES Nobel Prizes given for transplantation (19, if Anderson D, Billingham RE, Lampkin GH, Medawar PB. related immunology is included). In addition, 1951. The use of skin grafting to distinguish between this year’s to Tom Starzl and Roy monozygotic and dizygotic twins in cattle. Heredity 5: Calne brings to six the number of these presti- 379–397. gious awards for transplantation or related Anonymous. 1931. Apparatus to circulate liquid under constant pressure in a closed system. Science 73: 566. work. The distribution of these Prizes has not Barber WH, Mankin JA, Laskow DA, Deierhoi MH, been without controversy. Largely forgotten ri- Julian BA, Curtis JJ, Diethelm AG. 1991. Long term re- valries that enrich the story are those between sults of a controlled prospective study with transfusion of donor specific bone marrow in 57 cadaveric renal allo- www.perspectivesinmedicine.org Alexis Carrel and his colleague Charles Guthrie; graft recipients. Transplantation 51: 70–75. between the proponents of cellular immunity Belzer FO, Ashby BS, Dunphy JE. 1967. 24-hour and (Elie Metchnikoff, James B. Murphy, Leo Loeb, 72-hour preservation of canine kidneys. Lancet 2: 536– and Avrion Mitchison) and the champions of 538. humoral immunity (Paul Ehrlich, Peter Gorer, Belzer FO, Alessandro AM, Hoffman RM, Knechtle SJ, Reed A, Pirsch JD, Kalayoglum M, Sollinger HW. 1992. and others, even including Peter Medawar dur- The use of UW solution in clinical transplantation—A ing his early career); between transplant pio- four year experience. Ann Surg 215: 579–585. neers in Boston, Denver, and Paris, even between Billingham RE. 1991. Reminiscenses of a transplanter. In two separate teams of transplanters. However, it History of transplantation: Thirty-five recollections (ed. Terasaki P), pp. 73–91. UCLATissue Typing Laboratory, is notable and reassuring that in 1999, 12 of Los Angeles. the field’s surviving pioneers met to select and Billingham RE, Medawar PB. 1948. Pigment spread and cell agree on the “historical landmarks” briefly re- heredity in guinea pigs. Heredity 2: 29–47. viewed in this work (Groth et al. 2000) (Fig. 5). Billingham RE, Krohn PL, Medawar PB. 1951. Effect of cortisone on survival of skin homografts in rabbits. The promise of further progress toward the ul- BMJ 1: 1157–1158. timate achievement of tolerance is described in Billingham RE, Brent L, Medawar PB. 1953. “Actively ac- subsequent work. quired tolerance” of foreign cells. Nature 172: 603–606.

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www.perspectivesinmedicine.org Flexner S. 1914. Report on Cancer. Report of the Director of tivity to donor transplantation antigens. Transplantation Laboratories to the Scientific Directors. RURG 439. Rocke- 29: 429–431. feller Archives, p. 322. Rockefeller Archives Center, Sleepy Kaporian T, Sherman RA. 1997. A brief history of vascular Hollow, NY. access for hemodialysis: An unfinished story. Semin Gibson T,Medawar PB. 1943. The fate of skin homografts in Nephrol 17: 239–245. man. J Anat 77: 299–310. Kostakis AJ, White DJG, Calne RY.1977. Prolongation of rat Goldman M. 1987. Lister Ward, pp. 118–119. Hilger, Bris- heart allograft survival by cyclosporin A. Int Res Commun tol, UK. Syst Med Sci 5: 280. Goodwin WE, Martin EC. 1963. Transplantation of the kid- Ku¨ss R. 1991. Human renal transplantation memories, 1951 ney. Urol Surv 13: 229–248. to 1981. In History of transplantation: Thirty-five recollec- Gowans JL. 1957. The effect of the continuous reinfusion of tions (ed. Terasaki P), pp. 37–59. UCLA Tissue Typing lymph and lymphocytes on the output of lymphocytes Laboratory, Los Angeles. from the thoracic duct of unanesthetized rats. Br J Exp Ku¨ss R, Bourget P.1992. An illustrated history of organ trans- Pathol 38: 67–81. plantation: The great adventure of the century, p. 53. San- Gowans JL, McGreggor DD, Cowan DM. 1963. The role of dos, Rueil-maloncison, France. small lymphocytes in the rejection of homografts of skin. Ku¨ss R, TeinturierJ, Milliez P.1951. Quelques essais de greffe In The immunologically competent cell (ed. Ciba Founda- rein chez l’homme. Mem Acad Chir 77: 755–764. tion Study Group), Vol. 16, p. 20. Churchill, London. Ku¨ss R, Legrain M, Mathe G, Nedey R, Camey M. 1962. Groth CG, Brent LB, Calne RY, Dausset JB, Good RA, Homologous human kidney transplantation: Experience Murray JE, Shumway NE, Schwartz RS, Starzl TE, with six patients. Postgrad Med J 38: 528–531.

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Historical Overview

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Historical Overview of Transplantation

Clyde F. Barker and James F. Markmann

Cold Spring Harb Perspect Med 2013; doi: 10.1101/cshperspect.a014977

Subject Collection Transplantation

Heart Transplantation: Challenges Facing the Overview of the Indications and Contraindications Field for Liver Transplantation Makoto Tonsho, Sebastian Michel, Zain Ahmed, et Stefan Farkas, Christina Hackl and Hans Jürgen al. Schlitt Bioethics of Organ Transplantation Facial and Hand Allotransplantation Arthur Caplan Bohdan Pomahac, Ryan M. Gobble and Stefan Schneeberger Overview of Clinical Induction of Tolerance through Mixed Chimerism Jonathan C. Yeung and Shaf Keshavjee David H. Sachs, Tatsuo Kawai and Megan Sykes Immunological Challenges and Therapies in : Solid Organ and Islet Shruti Mittal, Paul Johnson and Peter Friend Marta Vadori and Emanuele Cozzi Clinical Aspects: Focusing on Key Unique Tolerance−−Is It Worth It? Organ-Specific Issues of Renal Transplantation Erik B. Finger, Terry B. Strom and Arthur J. Matas Sindhu Chandran and Flavio Vincenti T-Cell Costimulatory Blockade in Organ Lessons and Limits of Mouse Models Transplantation Anita S. Chong, Maria-Luisa Alegre, Michelle L. Jonathan S. Maltzman and Laurence A. Turka Miller, et al. Regulatory T-Cell Therapy in Transplantation: Effector Mechanisms of Rejection Moving to the Clinic Aurélie Moreau, Emilie Varey, Ignacio Anegon, et Qizhi Tang and Jeffrey A. Bluestone al. Opportunistic Infections−−Coming to the Limits of The Innate Immune System and Transplantation Immunosuppression? Conrad A. Farrar, Jerzy W. Kupiec-Weglinski and Jay A. Fishman Steven H. Sacks

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