World J. Surg. 2.:&.759-782.2000 DOl: 10.1007/s00268001012':&

History of Clinical Transplantation

Thomas E. Starzl, M.D., Ph.D. Thomas E. Starzl Transplantation Institute. University of Pittsburgh Medical Center. Falk Clinic. 4th Floor, 3601 Fifth Avenue. Pittsburgh. Pennsylvania 15213. USA

Abstract. The emergence of transplantation has seen the development of to donor strain tissues was retained as the recipient animals grew increasingly potent immunosuppressive agents, progressively better to adult life, whereas normal reactivity evolved to third party methods of tissue and organ preservation. refinements in histocompati­ grafts and other kinds of antigens. bility matching. and numerous innovations in surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft This was not the first demonstration that tolerance could be all of the organs and bone marrow cells in humans. At a more fundamen· deliberately produced. Analogous to the neonatal transplant tal level, however, the transplantation enterprise hinged on two seminal model. Traub [6] showed in 1936 that the lymphocytic choriomen­ turning points. The first was the recognition by Billingham. Brent, and Medawar in 1953 that it was possible to induce chimerism·associated igitis virus (LCMV) persisted after transplacental infection of the neonatal tolerance deliberately. This discovery escalated over the next 15 embryo from the mother or. alternatively. by injection into new­ years to the first successful bone marrow transplantations in humans in born mice. Howevt!r, when the mice were infected as adults. the 1968. The second turning point was the demonstration during the early virus was eliminated immunologicully. Similar observations had 1960s that canine and human organ allografts could self·induce tolerance been made in experimental tumor models. Murphy [7] reported in with the aid of immunosuppression. By the end of 1962. however. it had been incorrectly concluded that turning points one and two involved 1912 the outgrowth of Rous chicken sarcoma cells on the cho­ different immune mechanisms. The error was not corrected until well into rioallantoic membranes of duck or pigeon egg embryos. which the 1990s. In this historical account. the vast literature that sprang up could he reversed by inoculation of adult chicken lymphoid cells during the intervening 30 years has been summarized. Although admira· [8], whereas sarcoma implantation into adults was not possible. bly documenting empiric progress in clinical transplantation. its failure to explain organ allograft acceptance predestined organ recipients to The observations of Murphy and Traub did not influence the lifetime immunosuppression and precluded fundamental changes in the t!arly development of transplantation. Instead. the impetus and treatment policies. After it was discovered in 1992 that long.surviving rationale for the experiments of Billingham et al. [5,9] and similar organ tnmsplant recipients had persistent microchimerism. it was pos· ones in chickens hy Hasek [10] originated with Owen [II]. who sible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunolollY could then demonstrated that freemartin cattle [the calf equivalent of human be synthesized with which to guide efforts to induce tolerance systemati· fraternal (dizygotic) twins] hecame permanent hematopoietic chi­ cally to human tissues and perhaps ultimately to xenografts. meras if fusion of their placentas existed in utero. allowing fetal cross-circulation (Fig. I): such animals permanently accept each other's skin [12]. Burnet and Fenner [14] predicted that this How transplantation came to be a clinical discipline can be pieced natural chimerism and tolerance to other donor tissues and organs togethcr by perusing two volumes of reminiscences collected by could be induced by the kind of experiments successfully per­ Paul I. Tcrasaki during 1991-1992 from many of the persons who formed hy Billingham et al. Howt!ver. Billingham and Brent [15. were directly involved. One volume was devoted to the discovery 16] soon learned in mice_ parallel with similar observations by of the major histocompatibility complex (MHC). with particular Simonsen [17] in chickens. that tile penalty for infusing immuno­ reference to the human leukocyte antigens (HLA) that arc widely wmpetent hematopoietic cells was graft-versus· host disease used today for tissue matching [I]. The other focused on mile­ (GVHD) unless there was a close genetic relationship (i.e .. his­ stones in the dcvt!lopment of clinical transplantation [2]. All of the tocompatihility) between the donor and recipient. contrihutions descrihed in hoth volumes can he traced hack in one This was the beginning of modern transplantation immunology. way or other to the demonstration more than a half century ago by an extensive history of which has heen written hy Brent [I X]. one Peter Brian Medawur that the rejection of allografts is an immu­ of its principal architects. Each cell- and organ-defined branch of nologic phenomenon ]3 . .f]. transplantation also has had its historians. who huYe described the Ten years later (1953) Billingham. Brent. and Medawar [5] stages through which specific procedures moved to the bedside showed that tlllemnce to skin allografts Clluld he induced hy from experimental lahoratories-or in some cases directly. The inoculating Ictal or prenatal mice with immunocompetent spleen culminating clinical events can be capsulized with a list of the tirst cells from adult donors. Because of their immunologic immatu· ,>uccessful allotransplantation in humans of the kidney [19]. liver rity. the recipients were ineapahle of rejecting the spleen cells 120]. heart [21. 2:!\.lung 123]. pancreas (24]. intestine [25]. multi­ whose progeny survived indctinitely. Specitic nonresponsiyeness ple abdominal viscera [26]. and bone marrow [27-30]. 760 World J. Surg. Vol. 24, No.7, July 2000

Table l. Direction of acceptable organ transfer when the donor and luteum recipient have different ABO red blood cell types. r~ L. OVary ~, Red cell Transfer" Acceptability o Type II o to non-O Safe Rh- to Rh+ Safe Rh+ to Rh- Relatively safe ,---' A to non-A Dangerous I 1 B to non-B Dangerous , I AB to non-AB Dangerous I From Starzl [541. I "For organ transplantation. 0 is the universal donor and AB is the I universal recipient. With the transplantation of bone marrow allografts or I lymphoid-rich organ allografts (e.g., intestine or liver). enough anti-host I isoagglutinins may be produced by the allograft to cause serious or lethal I hemolvsis in a significant number of cases (humoral graft-versus-host disease [55]). Consequently. the rules summarized in this table are fully V applicable only with leukocyte-poor organs such as the kidney and heart (see section on Allograft Acceptance versus Acquired Tolerance).

Prehistory: Before Immunosuppression -::. Reciprocal An indelible mark on the pages of transplantation history was left with the perfection of techniques for organ revascularization using surgical anastomosis by Alexis Carrel at the beginning of the Fig. 1. Chimerism in freemartin (fraternal twins) described by Owen [I t 1. twentieth century [36]. Aside from the technical contributions. Cross-tolerance to formed blood elements followed intrauterine circula­ which provided the foundation for conventional vascular surgery. tal)' exchange in dizygotic twins. Mutual tolerance to skin grafts was later Carrel recognized that transplanted organ allografts were not proved by Anderson et al. with Medawar [121. (From Starzl and Butz [13J. with permission.) permanently accepted. although he did not know why. Using vascular surgical techniques. animal research on trans­ plantation was most highly focused on the kidney for most of the next half century [37-39]. The extrarenal vacuum rapidly was filled between 1958 and L960 with the development in several labora­ Although such milestones and dozens of lesser ones arc impor­ tories of canine models with which to study all of the intraabdomi­ tant. the emphasis in this account is on developments that were nal organs [40-44] and thoracic organs [45-47]. Although each applicable to all varieties of allografts and responsible for major organ presented specific technical and physiologic issues. the core transitions in transplantation ideology. It becomes apparent as the problems of immunosuppression. tissue matching. and allograft layers of history arc peeled away that §:ere were only two seminal preservation eventually were worked out mainly with the kidney turning points in the evolution of clinical transplantation. One was and liver and applied to other organs with minor modifications. the induction of chimerism-associated nconatal tolerance by Bill­ ingham. Brcnt. and Medawar in 1<)53. The sccond was the dcm­ onstration during 1%2-1%3 that organ allografts could self-in­ Hetero (Xcno) Transplantation duce tolerance ~ith the aid of im~unosuppressionJiill All The tirst known attempts at clinical renal transplantation by vas­ subsequent developments in organ transplantation depended on cular anastomoses were made hetween the beginning of the twen­ cxploitation of this principle. using variations of the drug strategy tieth century and 1923 in France [4X]. Germany [4<)]. and else­ that had made its discovery possible. Ironically. the down side of where (summarized in [50]) using pig. sheep. goat. and subhuman the resulting revolution in organ transplantation was the early primate donors. None of the kidneys functioned for long. if at all; introduction of a conceptual error that distorted the maturation of and the human recipients died a few hours to 9 days later. No transplantation immunology and adversely affected the orderly further animal-to-human transplantations were tried again until development of gcneral immunology. 1963. after immunosuppression was available 151. 521. The error. which was not corrected until well into the 1990s [32-3-i1. was thc conclusion by consensus that organ allograft Homo (,~"()) Trallsplallll/fioll acceptance IIlvolvcd mechanisms different from the chimerism­ dependent ones of neonatal tolerance and its clinical analogue III 11)36 Voronoy of Kiev. Russia. reported the transplantation of hone marrow transplantation. Consequently. the vast literature a kidney from a cadaver donor of B ,. hlood type to a recipient of that sprang up during the intervening 30 years admirably docu­ 0+ blood type [531. in violation of what han: hecome accepted mented the progression of improvements in clinical transPI'\2t:Jj rules of tissue transfer [5-i. 55] (Table I). III addition. the allograft tion while failing to explain what was being accomplished 351. was jeopardized by the residual risk of aeut!.! mercury poisoning Therefore the reader may protit by skipping III the last section of (from a suicide attempt). which had caus!.!d the recipient's renal this article (Allograft Acceptance versus Acquired Tolerance) failure. A tinal advers!.! factor was (ile 6-hour laps!.! b!.!tween the hefore attempting to understand what went on hetween 1963 and donor's death and organ procurcment. Th!.! allograft did not Il)ll3 and hefore. produc!.! any urine during the -is hours of tht: palit:nt's posttrans- Stanl: History of Clinical Transplantation 761 plant survival. Although other attempts may have been made by John Merrill. who remained in Boston. drowned off the beach of Voronoy [56], another 15 years passed before significant kidney a Caribbean island in 1984. transplant activities were resumed in France. None of the European and American efforts to this time. or all In 1952 Rene Kuss [57J and Charles Dubost [58] in Paris and togt!ther. would have had any lasting impact on medical practice Marceau Serve lie [59J in Creteil carried out a series of renal were it not for what lay ahead. The principal ingredients of organ transplantations with kidneys removed from convict donors im­ transplantation-immunosuppression. tissue matching, organ mediately after their execution by guillotine. The next year. the procurement (and preservation)-were still unknown or undevel­ French nephrologist Jean Hamburger. in collaboration with urol­ oped. The only unequivocal example of clinically significant allo­ ogist Louis Michon at the Hopital Necker in Paris. rcported a graft function through 1954 was provided by one of the nonim­ mother-to-son transplantation of a kidney that functioned well for munosuppressed patients of Hume et al. [62) whose thigh kidney 3 weeks before being rejected [60). The procedure developed by produced life-supporting urine output for 5 months. Similar Kuss and the other French surgeons and used for this first live claims about function of an allograft transplanted to the ortho­ donor kidney transplantation has been performed hundreds of topic location [68] (i.e., as in Doolittlc's case (62)) or to a non­ thousands of times since then. The operation's relative freedom anatomic site [69] were considered implausible by later critics. from chronic morbidity would soon be dcmonstrated with the The existence of these cases was public knowledge. but the identical (monozygotic) twin transplantations of Joseph E. Mur­ failure of all the grafts (usually with death of the patient) left little ray and John Merrill and their associates [61 J at the Peter Bent room for optimism. The perception. if not thc reality. of hopc­ Brigham Hospital in Boston. lessness was changed at the Petcr Bent Brigham Hospital 2 days The etIorts by the French teams were widely known. and visitors before Christmas 1954 when a kidnt!y was removed from a healthy flocked to Paris during the early 1950s to learn first-hand from the man by urologist J. Hartwell Harrison and transplanted by Joseph experience. One of the observers of the extraperitoneal pelvic E, Murray 10 the pelvic location of the donor's uremic. identical operation (often called the Kuss procedure in Europe) was John twin brother [61. 70]. Although no effort was made to preserve the Merrill. as Hume and Merrill et al. (62) described in their account isograft. it functioned promptly despite 1-l2 minutes of warm isch­ of the first clinical trials at the Peter Bent Brigham Hospital. emia. The recipient lived for nearly 25 years before dying of Among Hume's nine Boston cases. howt!ver. all but one of the atherosclerotic coronary artt!ry disease. allografts were placed in the recipient thigh. revascularized from According to Merrill et al. [61]. exploitation of genetic identity the femoral vessels, and provided with urinary drainage by skin for wholt! organ transplantation had bcen suggested by the recip­ ureterostomies. ient's physician. David C. Miller. of the Public Health Service The exceptional case in the Boston series [62J was the first one. Hospital. Boston. It already was well known that identical twins The donor and recipient opt!rations were performed in Spring­ did not reject each others' skin grafts [71). To ensure identity. field. Massachusetts. on March 30. 1l)51. by L.H. Doolittle. The reciprocal skin grafting was performed in the Boston twins. Al­ donor kidney. excised because of a carcinoma of the lower ureter, though the identical twin cases attracted worldwide attention. was implanted in the vacated renal fossa of the recipient after organ transplantation now had reached a dead end. Further removing the native organ. The recipient patient had been under progress in the presence of an immunologic barrier would require short-term dialysis care at the Brigham. where the first artificial clfectivc immunosuppression. The possibility of meeting this ob­ kidney in the United States had been brought from Holland by jective could only be regarded as bleak. To understand why, it is Wilhelm Kolff and modified by Harvard engineers. as described in necessary to appreciate not only how harren the landscape of detail by Moore [63J. immunology was but also how slowly the prcexisting information The next eight operations. in which the allografts were placed in had been filled in. the anterior thigh. were performed by Hume in Boston between A century had passed between the tirst vaccination procedure in April 23. 1951. and December 3. I \}52. The rcport of the nine 17\}6 (Edward Jenner. small pox) and confirmation of the immu­ cases stands as one of the medical classics of the twentieth cen­ nization principle by Louis P4Isteur (with chicken cholera and tury. providing an extensive clinical and pathologic profile of renal rabies). The proof obtained by Robert Koch that microorganisms allograft rejection in untreated human recipients. The descrip­ caused anthrax (11i76) and subsequently many other infectious tions compI.:mented the report of Michon and Hamburger of the diseases stimulated a search for the host's protective mechanisms. live-donor French case (set! earlier [hO!) and pathfinding studies This search yielded components of the immune response: anti­ in dogs hy Morten Simonsen in Denmark PHI and of W. James hodies [Emil Adolf Von Behring and Shibasaburo Kitasato Dempster in England [J\}J. It is noteworthy that Hume treated (11i\}O)I. immune cells [llya Metchnikolf (11i1i4)1. and complement some of his patients with adrenal cortical steroids. It was alreadv [Jules Bordet (ISl):'i)j. In addition. Paul Erlieh developed the side known from experimental studies that stcroid therapy modestly chain theory (I:-il)()). according to which each cell has a vital celller mitigated primary skin graft rcjection [h-!-h61 and even slowed of protein substance and a series of side chains (later known as the accelerated rejection of presensitized recipients Ih7J. receptors 1 to which toxic suhstanccs and nutrients were absorbed Although Cllmpilation of the Boston scries postdatcd the early and then assimilatcd. In 1910 Erlich introduced the tirst antimi­ French elIorts (as generously annotated hv Humc I. the commit­ LTooial drug. antibodies wcrc produced in each individual only until his dcath in the crash lIf a private plane (of which he was thc III those antigens to which he or she was exposed [14J. The lack of pilot) ncar LllS Angelcs in Mav 1'17.'. illS friend and colleague. major movement between events IS eVident from

Table 2. Nobel Prizes related to immunology/transplantation.

Year Name Accomplishment 1901 Emil Adolf Von Behring Discoverv of antibodies 1905 Heinrich Hermann Robert Koch Cause ,!I;d <.:trect of microorganisms and infection 1908 Paul Ehrlich Side chain (receptor) concept: champion of humoral immunity: antimicrobial therapy I1ya Metchnikoff Champion of cellular immunity 1912 Alexis Carrel Vascular surgery and transplantation 1919 Jules Bordet Discoverv of complement 1930 Karl Landsteiner Discover~d ABO blood group antigens 1960 Sir Frank MacFarlane Burnet Clonal selection hypothesis Sir Peter Brian Medawar Acquired transplantation tolerance 1972 Gerald M. Edelman Characterized immunoglobulins Rodney R. Porter Clarified structure of a'iitibodv molecule 1980 Baruj Benacerrat Discovered immune response" genes and collaborated in discovery of major histocompatibility complex (MHC) restriction Jean Dausset Discovered first HLA antigen George Davis Snell Discoverv of MHC in mice 1984 Niels Kaj Jerne Importa~t immunologic hypotheses Georges I.F. Kohler Hvbridoma technologv Cesar Milstein Hybridoma technology 1985 Michael Stuart Brown and Hepatic control of cholesterol metabolism (with Goldstein)" Joseph Leonard Goldstein 1987 Susumu Tonegawa Discovered somatic recombination of immunologic receptor genes 1988 Gertrude Belle Elion and Co-discovery (with Hitchings) of 6-mercaptopurine and George Herbert Hitchings azathioprine 1990 Joseph E. Murray Kidney transplantation E. Donnall Thomas Bone marrow transplantation 1996 Rolf Zinkernagel and Peter C. Doherty Co-discovered (with Doherty) the role of MHC restriction in adaptive immune response to pathogens

From Schlessinger and Schlessinger [72]. © 1991. with permission of Oryx Press. ~()41 N. Central Avenue. Suite 700. Phoenix, AZ 85012; 800-279'0799. "Proved with liver transplantation for indication of hypercholesterolemia (73. 7~].

Prizes [72) (Table 2). Although 6 of the first 17 Nobel laureates mune system? This idea was tested in rabbits during 1950-1951 (1901-1919) were honored for work relevant to immunology/ with cortisone [64. (5) and total body irradiation [76). Both tech­ transplantation. there was only one more example (Karl Land­ niques prolonged skin graft survival for only a few days. steiner, ABO blood groups) among the next 57 (\ 920-1 (59). Neither these results. nor those reported with cortisone in 1952 Beginning with Burnet and Medawar (see above). 17 of the 77 by Cannon and Longmire [66) in a chicken skin graft model laureates since 1960 have been directly responsible for. contrib­ generated much optimism. However. the Cannon-Longmire re­ uted to. or directly benefited from, advances in transplantation port contained three observations that, in retrospect, presaged not (Table 2). only the acquired neonatal tolerance produced by Billingham, In Burnet's original hypothesis of immunity. antibody synthesis Brent. and Medawar the following year but also the most impor­ was postulated to occur after an antigen locked onto a membrane­ tant clinical advances in transplantation of the succeeding de­ bound receptor (a version of the antibody) displayed at the sur­ cades. First, skin grafts exchanged between I-day-old chicks of face of an immune cell. After binding the antibody. the cell ditferent breeds had a high rate of initial engraftment and a 6% proliferated. producing a clone that secreted identical antibodies incidence of permanent take. Second. the window of neonatal (the clonal selection theory). Nossal subsequently proved that the opportunity was gone by 4 days. Third, and most important. the clone rose from a single cell ("one cell/one antibody") [75). Al­ percent of permanent engraftment of neonatally transplanted skin though Burnet's hypothesis was not yet complete. it was to be­ \Vas increased to more than 20% by a course of cortisone. with no come the cornerstone of modern immunology. increase of mortality. The significance of the third observation was recognized by Concept of Immunosuppression Cannon and Longmire who wrote: ":'\/though the cortisone did not entirely prevent a reaction in the homograft, it did decrease With Recipiem Cytoablatioll the incidence of reaction. Even more important. the increased incidence of reaction [sicl free grafts appeared to maintain itself The transition of tissue and organ transplantation from an exer­ after the drug was discontinued. This phenomenon is one which cise in futility to tenuous practicality involved a surprisingly small lip to the present time has not been found in homograft experi­ number of advances. which were interspersed over long periods of ments on mammals and humans." frustration. After Medawar's demonstration in 1044 that rejection Despite a confirmatory follow-up study in 1957 [77], the ne­ was an immunologic event [3. 4). a logical and inevitable question glected Cannon-Longmire article faded quickly from the collec­ was: Why not protect the organ allograft hy weakening the il11- tive memory of both hasic scientists and clinicians. In contrast. the Starzl: History of Clinical Transplantation 763 achievement of acquired neonatal tolerance by Billingham et ai. in Table 3. Kidney transplantation with 2: 6 months survival as of March 1953 [5, 9] ignited interest in transplantation as never before. Two 1963. years later, Main and Prehn [78] attempted to simulate in adult Survival mice the environment that allowed the acquisition of neonatal Case City" Refs. Date Donor (months)" tolerance. The three steps were (1) to cripple the immune system Boston 19.86.87 1/24/59 Fraternal twin > 50 with supralethal total body irradiation (TBI): (2) to replace it with -, Paris 88.89 0129159 Fraternal twin > 45 allogeneic bone marrow (producing a hematolymphopoietic chi­ 3 Paris 90 6/22/60 Unrelated' 18 (died) mera); and (3) to engraft skin from the same inbred strain as the 4 Paris 89 12/19/60 Mother 12 (died) 90 3112161 Unrelated' 18 (died) donor of the bone marrow. 5 Paris (, Paris 88 2/12/62 Cousin' >13 The experiments were successful [79, 80]; but as with the neo­ 7 Boston 87. 111 4/5162 Unrelated 10 natal tolerance model, lethal GVHD could be avoided only when UBoston: J. E. Murray (cases 1, 7); Paris: J. Hamburger (cases 2. 4, 6) there were "weak" histocompatibility barriers. Applying the chi­ and R. Kuss (cases 3. 5). merism strategy for kidney transplantation in beagle dogs in Coo­ hThe kidneys in patients I. 2. and 6 functioned for 20.5. 25, and 15 perstown, New York, Mannick et al. [80] reported good renal years. respectively. Patient 7 rejected his graft after 17 months and died allograft function in a supralethally irradiated recipient, which after return to dialysis. also was given donor bone marrow and was a hematolymphopoi­ 'Adjunct steroid therapy. etic chimera; the animal lived for 73 days before dying of pneu­ monia. Because it was demonstrated later that this outcome de­ pended on the identity of the dog lymphocyte antigens (DLA) [81. 82], an accidental DLA match was suspected in retrospect to have renal function from the time his fraternal twin brother's kidney been present in Mannick's experiment. Efforts by Hume et ai. [83] was transplanted on January 24. \lI59 until he died in July 1979 and subsequently by Rapaport et al. [84] and others to broaden (Table 3). With this historical accomplishment. the genetic barrier the range of acceptable histocompatibility inevitably led to lethal to organ transplantation had been definitively breached for the GVHD, rejection, or both. first time in any species [19]. Five months later Hamburger et al. [88] added a second fraternal twin transplantation, using the same Bone Marrow Transplantation. With the impasse. workers in bone treatment (Table 3). This second recipient had good renal func­ marrow and whole organ transplantation took separate pathways. tion until his death 26 years later from carcinoma of the urinary Bone marrow transplantation was dependent a priori on the bladder. classic chimerism-associated acquired tolerance induction defined In these two dizygotic twin cases, it was conceivable that the at the outset by Billingham. Brent, and Medawar in the neonatal donor and recipient placentas had fused during gestation, analo­ model. Despite the fact that only highly histocompatible donors gous to Owen's freemartin cattle (see ahove and Figure I). This could be used. clinical success with bone marrow engraftment was suspicion was put to rest at the Paris centers of Jean Hamburger achieved in 1963 by Mathe et ai. in Paris [27], whose patient lived [89] and Rene Kuss (90] by four more examples during 1960-\962 for 2 years with chronic GVHD before committing suicide. of survival of more than I year. In Kuss's two cases the donors Five years later, Gatti and Good et al. in Minneapolis [29] and were not related (Table 3). During the critical period from Jan­ Bach et al. at the University of Wisconsin (28] each transplanted uary 1959 through the spring of 1962, the cumulative French hone marrow to recipients who are well today. The lifetime ell'orts experience was the principal (and perhaps the only) justification of Thomas [30], van Bekkum [85], and others fueled the matura­ to continue clinical trials in kidney transplantation. tion of hone marrow transplantation into accepted clinical therapy The experience from Boston and Paris summarized in Table 3 for numerous hematologic diseases (including malignancies). ac­ showed that bone marrow infusion was not a necessary condition quired immune deficiency disorders. mesenchymally hased inborn for prolonged survival of kidney allografts and ostensibly elimi­ errors of metabolism. and an assortment of other indications. Bone marrow transplantation was an intellectual triumph. Its nated the requirement of chimerism. The stage was set for drug therapy. In fact, hath Hamhurger and Kuss mentioned the use of development could be traced in a straight line back to the exper­ iments of Main and Prehn [78] and before that to the acquired adrenal cortical steroids as an adjunct to TBI (Table 3): but neonatal tolerance of Billingham. Brent. and Medawar [5. 91 and neither the dose nor thc indication for the steroids was described. the natural tolerance of Owen's freemartin cattle [II]. In addition. Kuss secondarily administered 6-mercaptopurine (6- MP) to one of his cytoahlated patients as early as August 1%0 W'hole Organ Transplalllotion. In contrast. clinical organ trans­ [<)0]. "on the basis of the recent results of the experimental studies plantation. the wide clinical use of which preceded hone marrow conducted by Caine" [9 I] (sec also next section), Calm: had made transplantation by a decade. appeared to be uisconnected from a an invited visit to the Paris center a few months earlier (R. Kuss rational base when it was concluded that organ engraftment seem­ and R. Caine. personal communication). ingly was independent of chimerism. An extension of the Main­ Some authorities have considcreLl irradiation-induceLl and Prehn strategy (i.e .. lethal TBI followed hy bone marrow and drug-induced graft .Icceptance to he dilkrent phenomena 150. X7. kidney allografts. as in Mannick's dog) was used by Murray et al. 92]. More recently. it has hecomc obvious that the variable de­ [86] in only two cases. both in IlI58. The next 10 kidney recipients grees of graft acceptance achieved with sublethal TBI hetween in Boston were conditioned with slthll't/wl TBI wi/how hOIlC mar­ January 1959 anLl February I %2 were fundamentally the same as row [19.86.87). Eleven of the twelve irradiated patients died after that seen in tens of thousands of drug-treated humans following o to 28 davs. transplantation of various whole organs (sec Allograft Acceptance The surviVor (who was not given bone marrow) had adcquatc \crsus Acquired Tolerance). 764 World J. Surg. Vol. 24, No.7, July 2000

With Drug Immunosuppression [87]. Only one of the first I () kidney recipients treated with either 6-MP (/I = 2) or azathioprine-based immunosuppression (n = 8) After it was learned that TBI alone could result in prolongation of survived more than 6 months (the last one in Table 3) [87, 111]. kidney allografts, it was logical to focus the search for immuno­ At the nadir of the resulting pessimism. two reproducible ob­ suppressive drugs on myelotoxic agents whose effects mimicked servations. first in dogs and then in humans. were made at the those of irradiation. In September 1960 Willard Goodwin of Los University of Colorado. Taken together. these findings profoundly Angeles produced severe bone marrow depression with metho­ shaped future developments in transplantation of all organs and trexate and cyclophosphamide in a young female recipient of her eventuallv of hone marrow. The observations were encapsulated mother's kidney. The patient subsequently developed multiple in the titie of a report puhlished in October 1963: "The Reversal rejections that were associated with bone marrow recovery. They of Rejection in Human Renal Homografts with the Subsequent were temporarily reversed with prednisone several times during Development of Homograft Tolerance" [3\). the 143 days of survival. It was the first example of protracted The reversal was readily accomplished by temporarily adding human kidney allograft function with drug treatment alone [93]. unprecedented high doses of prednisone (200 mg/day) to baseline However. the case was not reported until 1963. immunosuppression with azathioprine. The evidence that the liv­ Kidney transplant surgeons were quick to realize that bone ing donor kidneys had self-induced tolerance under an umbrella marrow depression should be avoided. not deliberately imposed. of immunosuppression was equally clear. Most of the recipients following the demonstration by Schwartz and Dameschek [94] had a subsequent progressively diminishing need for immunosup­ that 6-MP in a nontransplant rabbit model was immunosuppres­ pression. usually to doses lower than those that initially failed to sive in submyclotoxic doses. Within a few months after their prevent rejection. Thc tolerance was complete enough to allow seminal discovery. Schwartz and Dameschek [95] and Meeker [96] the patients to go home to an unrestricted environment. Nine of (working with Condie. Weiner. Varco. and Good) showed that the first ten of these kidney recipients achieved prolonged graft 6-MP caused a dose-related delay of skin graft rejection in rabbits. survival [31]. including two who hear the longest continuously Aware of these results but independent of each other. Caine [97] functioning allografts in the world today (more than 35.5 years) in London and Zukoski. Lee, and Hume [98] in Richmond. Vir­ and have been free from immunosuppression for 32 and 4 years. ginia. demonstrated the same thing in the canine kidney trans­ respectively [109]. plant model. In June 1960 CaIne moved from the Royal Free The practical and theoretic implications of these observations Hospital to join Murray at the Peter Bent Brigham Hospital were recognized throughout the report [31]: (Boston) for further preclinical studies of 6-MP and its analogue azathioprine [87. 99-101]. A state uf relative immunologic non-reactivity seems to have been pro­ duced which has lasted for as long as h months .... It is not knuwn whether The two drugs had heen developed originally by Gatrude Elion this is due to a change in the antigenic properties of the homograft. or to and George Hitchings as antileukemia agents [102]. Their possihle an alteration in the specific [hostl response to the stimulus of the grafted use for transplantation was greeted at first with feverish enthusi­ tissues. The apparent host-graft adaptation does. however. provide some asm hecause it was generally conceded that recipient cytoablation hope for prolonged functional sUlVival. . .. It wuuld seem probable that the [thaapeuticj principles. as ddined with the kidney. can eventually be would permit success in only occasional cases of human renal applied tu other organ homografts .... The prior knowledge that a rejec­ transplantation. Although approximately 95 c,{ of the mongrel ca­ tion crisis is almost a certaintv and that it usuallv can be managed bl' nine kidney recipients treated with 6-MP or azathioprine died relativelv const:lVativt: means shuuld SCIVC as a deterrent to the cx~essiv~ within less than 100 days from rejection or infection. occasional usc of measures that may cause fatal bone marrow depressiun .... It is examples were recorded of long-term or seemingly permanent also conceivahle that the avoidance of a primary host-graft reaction bv thest: means lexcessive immunmupprcssionj would prevent the adaptive allograft acceptance [103-106] following discontinuance of a 4- to process. 12-month course of immunosuppression. The number of these animals was discouragingly small, hut it was an accomplishment At the time this hellwether series was compiled hetween the never remotely approached using TBI. with or without adjunct autumn of 1962 and April 1%3. the only other active clinical hone marrow. Survival of Mannick's single cytoablatcd animal for transplantation programs in the United States were in Richmond 73 days after comhined hone marrow and kidney transplantation (directed hy David Hume) [110] and at the Peter Bent Brigham had been the previous high water mark in dogs (see earlier [HO]). Hospital in Boston (directed hy Joseph Murray and John Merrill) The survival of some of CaIne's animals beyond 6 months led to [Ill]. The important earlier program of Willard Goodwin at the decision at the Brigham to begin clinical trials with chemical UCLA (see earlier [9,1]) had heen closed hecausc all of the immunosuppression. However, the poor therapeutic margin of the recipients died in less than 5 months. 111 Europe. TBI brietly 6-MP and azathioprine when used alone in dogs was recognized. remained the prderreu treatment at the long-standing Paris cen· Caine and Murrav also were forewarned hy an earlier clinical ters of Jean Hamhurger and Rene Kuss. whereas Michael Wood­ experience of Hopewell. CaIne. and Beswick [107]. which was not ruti' of Edinhurgh had hegull testing azathioprine [112]. puhlished until I %~. in which 6-MP had been used to treat three The results in the Colorado series. and more importantly an kiunev recipients (including one with a living donor) during 1959- exact description of the strategy that had been used to induce 1()60: all three recipients had died. variable degrees of incomplete tolerance (Table ~). created a Consequently. the canine studies of 6-MP and azathioprine in surge of new activity. Within 12 months new kidney transplant Boston were highly focused on finding more dt'cctive drug com­ centers proliferated in North America and Europe. Most of these hinations [1'17. lJlJ. 10 l. 10H]. Although :Idrenal cortical steroids s<.:cond-generation programs remain in oper:ttion today. were tested. they did not appear to potentiate the value of aza­ The ohservations in the original kidney recipients were thiopnne [Ill). to II. prompting Murrav in hiS clinical trial to opt promptly contirmed. However. the proposed explanation for these for adjunct cytotoxic agents such as azaserine and actinomycin C ,uccesscs (i.e .. grail alteration plus loss of specitic immunologic Starzl: History of Clinical Transplantation 765

Table 4. Empiric therapeutic dogma of immunosuppression. Most convincingly at an experimental level. it was shown in I t}64 that orthotopic canine liver allografts could induce and Ingredients of strategy Baseline agent maintain their own acceptance far more frequently and perma­ Baseline therapy Azathioprine" nently than renal allografts. even with a treatment course of Secondary adjustments of prednisone dose. or Cvclosporine azathioprine as short as 4 months [123, 124]. Soon thereafter. antilymphoid agents" Case-t~-case trial (and potential error) of Tacrolimlls spontaneous engraftment was demonstrated after liver transplan­ weaning tation in untreated outbred pigs [125-129]. many of which passed through self-resolving rejection crises [128, 130. 131 J. "Alom: or with prophylactic prednisone. Equivaknt n:sults were ob­ tained with cyclophosphamide instead of azathioprine [I D. Ilol]. Thus it already was clear by 1964-1965 that the liver is the most I>lnitially used for prophylactic "induction" [115]. to\erogenic organ. During the late 1960s and early 1970s. CaIne, Zimmerman. and Kamada formally proved that the liver toleriza­ tion extended to other donor tissues transplanted at the same time responsiveness [31]) was controversial and remained so for the or later. first in untreated outbred pigs [132] and then without next three decades (see Allograft Acceptance versus Acquired immunosuppression in selected rat strain combinations [133-135]. Tolerance. below). Except for reports from the University of Although they were important. the experimental studies with Colorado. the term "tolerance" was studiously avoided from 1%4 hepatic allografts only affirmed the conclusion reached with the onward when referring to the long-surviving dogs and human 1962-1963 experience in clinical renal transplantation suggesting kidney recipients produced by the end of 1963. that all organs were capable of inducing tolerance. As with liver The article most often quoted as contravening tolerance was allografts. the self-induction of donor-specific tolerance by heart that of Murray et al. [106] despite the fact that. as the authors took and kidney allografts without the aid of immunosuppression was pains to make clear. the evidence in their report was inconclusive later demonstrated by Corry et al. [136J and Russell et al. [137] in and involved only two canine experiments of a potentially crucial selected mouse strain combinations. nature. The two long-surviving dogs had been given renal ho­ The key mechanism of kidney-induced allograft acceptance was mografts 9 and 18 months previously and had been treated for suggested as early as 1964 to he clonal exhaustion [138J. This most of these times with one of the purine analogues. Renal concept was developed more fully for liver allografts in Figure 2. function was deteriorating at the time contralateral kidneys from published in 1969 [139]. Induction of the activated clone by al­ the original donors were transplanted. The second organs were loantigen was depicted via host macrophages rather than by an­ rejected after 23 and 3 days. respectively. as would he expected. tigen-presenting dendritic cells. which would not be described In commending Murray's 1964 report and conclusions. Me­ until 1973 [140]. In the text accompanying the figure. it was dawar wrote [116JI: pointed out that exhaustion and deletion of an antigen-specific There is. however. something special about renal homografts. as JMichaelJ clone had been postulated by Schwartz and Damesehek as early as Woodruffs appraisal in this volume makes very clear. A synoptic survey of 1959 to be the mechanism of the tolerance to heterologous pro­ more than 1000 renal homografts in dogs carried out bv Murrav and his tein induced in rabbits with the aid of h-MP [94]. In addition. colleagues [Murray. Ross Shiel. Mosele~v. Knight. McGavic & Dammin. Simonsen had suggested in 1960 that clonal exhaustion induced by 1964][ J06] has shown that foreign kidneys do sometimes become accept­ able to their hosts for a reason other than acquired tolerance in the allogeneic splenocytes could lead to the acquisition of tolerance in technical sense .... There has been an adaptation of some kind-a pos­ adult animals in the absence of immunosuppression (I ~ I J. sihility Woodruff has long urged us not to overlook [117. 11 H] thougll there The error of making a semantic distinction between tolerance is no reason to believe it an antigenic adaptation. and graft aCCl:ptance was understandable. The picture that had One possible explanation is the progressiv..: and perhaps very extensive cmerged from the remarkahle acwmplishments with clinical kid­ r<:plac<.:ment of the vascular endothelium of the graft bv cndoth<.:lium of host origin. a process that might occur insidio-usly aild imperceptiblv ney transplantation between January 1959 and the spring of 1963 during a homograft reaction weakened by immunosuppressive drugs .... was not a product of new insight in immunology. Instead. success­ Another possibility. raised by R.Y. CaIne Jthough not mentioned by him ful organ transplantation was an intellectually troubling and inex­ in his contribution to this volume I is the laying down of a protectiv..: coat plicable violation of the immunologic rules of the time. The of host antibody on the endothelial inm:r surface of the graft-an expla­ nation which would classifv the plll:nomenon under the general heading of revolution in immunology that had already begun and would "enhancemcnt.·· continue for the next third of a century did little to change this vtew. These disclaimers notwithstanding. the commonality of the re­ The Burnet antihody hypothesis of clonal selection (see earlier jeetion barrier for different organs was self-evident. as was the [I~]) was validatcd and extended to cellular immunity by the late likelihood that the means of inducing acceptance of one organ 1950s [142-144J. but it had minimal intluence on the clinical could be used for all the others [119J. There also was evidence development of transplantation. Neither did many other kcy ad­ from earlier experiments that a liver allograft could protect other vances in immunology which were either contemporaneous with. donor tissues and organs. It had been noted in 1%2 that intestine ur came after. the rise of organ transplantation. The role of the and pancreas had little histopathologic evidence of rejection in thymus in the ontology of the immune system and in the postnatal untreated canine recipients if they were components 01 multivis­ immune function of rodents was discovered in 1961 (by Jacques ceral allografts that also included the Ii\'er [120J. These observa­ Miller [145. 14(1). However. thymectomy in humans did not sig­ t ions were contirmed J() years later in a rat version 01 the same nificantlv alter either the early or late course of kidney transplant multivisceral procedures [121. 1221· recipients [147. 14XI. Lymphocytes were not formallv assigned a functionunul I%J (by James Gowans [149.150]). although work­ 'Original numhers in the 4uolI: ha,'e heen changed to those of curn:nt ~'rs in transplantation were awarc several years earlier that these rdcrencc liSt. The 4uotaUlln IS llth<':fwl,e \crh'\llm. mononuclear leukocytes \\ere the cellular agents of allogralt re- 766 World J. Surg. Vol. 24, No.7, July 2000

T. .. ,~... ;,;~~$i<~. ...11-.

,,~

Lymphocytes _ e _ ~ Fig. 2. 1969 hypothesis of ,-J---, r---L-,,-L-, ~ I I allograft acceptance by clonal exhaustion. Antigen presentation • •• (f!) ~ ~. .,,::~~ ~ '. IJI> ~ was depicted via the macrophages ....------....,-.------.,...-....,. .. ~~ ... ------~ rather than bv the dendritic cells Immune -.-~ ------.-."::::.·~::i~~__ r=...... ~. ., ------>__ (which had n~t vet been described). A gap in this Suppression ~= =- =- -=- -=- -=-----~~~~~X~)h ~ -=------::=~ hypothesis was the failure to '------~ .. ------>- -- -,/ -- T ------> stipulate the location of the immune activation. (From Starzl Immunoglobulins [139]. with permission.)

water HOST DEFENSE Tissue Electrolytes Lymphocytes lSerum proteins ~. Humoral antibodies ~~r.----r~ / \ ' r----~ B

Top view Cross section

Fig. 3. Diffusion chamb<:r us<:d in studi<:s by Algire et al. [151). from Bacteria IMMUNOSUPPRESSION Bacteria which tlll:y cllnciud<:d that lymphocytes w<:r<: the cellular agents of allo· (peak at rejection crisis) graft rejection. (From Slarzl and Blitz [1J). with permission.) Fig. 4. Possible mechanisms of simultaneous loss of host reactivitv III specific strains of ~ndllgenous bacteria and to the alien renal tissue. (F'rum jection [1.1. 151. 1521 (Fig. 3). By the time the distinction was Starzl et al. [15-1). with permission.) clearly established between T and B lymphocytes. transplantation was an established specialty of clinical medicine. Thus [he ascension of organ transplantation came as a surprise ing its reach to the replacement of vital organs other than thc to most immunologists. Even as the clinical advances had begun to kidney. unfold. Burnet [I ~~] had written in the New Englund lvumal or One dikmma. as it was perceived at the time. is shown in Figure Medicinc that "much thought has been given to ways by which ~ [1541. It was kared that chronic drug immunosupprcssion pow­ tissues or organs not genetically and antigenically identical with erful enough to prevent organ allograft rejection would render the the patient might he made to survive and function in the alien recipient hopelessly vulnerable to indigenous and environmental environment. On the whole. the present outlook is highly unfa­ pathogens. Early reports of infectious disease complications in the vorable [0 succcss:· Pessimism also was deeply ingraincd in con­ early Colorado recipients [1551 and elsewhere gave warning that ventional practitioners of medicine. Well into the 1l)6()s editorials dire consequences might. in time. bc in store for all recipients. It were published in major clinical journals questioning hoth the ~dso was suspected that immunc surveillance to tumors would be inherent feasibility and the ethnical basis ot transplantation pro­ eroded. a possibility that was veri tied but shown to be manageahk cedures 1153]. As a consequence. transplantation acquired a ren­ by IlJ6H [156-1 :is]. egade Imagc. a burdcn soon compounded by dilticulties in extend- .\utopsy studies in faikd clinical cases revcakd a typical pat- Starzl: History of Clinical Transplantation 767

tern. Infections for which specific antibiotics were available could In most of the animal investigations up to 1963 the anti-lym­ be largely controlled. However. opportunistic microorganisms of phocyte antibodies were raised in rabbits; and raw ALS was normally low pathogenicity were overrepresented and appeared at administered to all recipients. In preparation for clinical trials, autopsy to be the main cause of death [159]. Of these infections. horse anti-dog ALS was prepared. and the active moiety was cytomegalovirus (CMV) was the most common and most lethal. refined from the gamma globulin [162]. After the product was The presence of Pneumocystic carillii as a co-infection with CMV shown to inhibit or reverse rejection in the canine kidney and liver [160] premonitored the lethal role of this combination of infec­ transplant models [I 15], comparable horse anti-human ALG was tious agents in the AIDS epidemic in the nontransplant popula­ produced from the serum of horses immunized with leukocytes tion that lay two decades ahead. separated from human lymphoid organs (lymph nodes. spleen. thymus) [162]. The first clinical trial of ALG began in 1966. Daily injections Maturation of Transplantation were given to kidney recipients for 1 to 4 weeks postoperatively as a short-term adjunct to continuous azathioprine and prednisone Although it was entirely empiric. the practical framework re­ [115]. After encouraging results were obtained in the kidney trial, quired for the maturation of clinical transplantation was essen­ liver transplantation was resumed, with long survival of several tially complete by the end of 1963. Without knowing either the patients. The successful liver replacements during the summer of nature of the normal immune response or the way in which it had 1967 [20] expanded the horizon of transplantation to the other been subverted, it had been learned how to redirect the immune vital extrarenal organs. Within the succeeding 27 months. heart response reliably with the aid of immunosuppression. Surgical [21, 22], lung [23]. and pancreas [24] transplantation was accom­ (see above) and preservation techniques (see later) had been plished. using variations of the treatment shown in Table 4. As developed for transplantation of all of the organs and are used had happened with kidney centers in 1963, a wild proliferation of currently wi th only minor modifications. Yet the field of organ extrarenal (particularly heart) programs followed. However. al­ transplantation stalled and now entered a phase that was euphe­ most all of them closed within the next 2 years because of an mistically tcrmed "consolidation." The reason was the failure to overwhelming failure rate. find improved means to exploit the principles for controlling Polyclonal ALG was never used in more than about 15% of rejection that had been established with azathioprine and pred­ kidney transplant cases reported to registries up to the early nisone (Table 4). 1980s, in part because it was in no sense a standardized drug such as azathioprine or prednisone. Although the use by Najarian and Improwd ImmunoslIppression Simmons [176] of known numbers of cultured human Iympho­ blasts for accurately timed horse immunization improved the Anti(vmp/lOid Strategies. Between 1963 and 1979 the only signifi­ predictability of the ALG potency, batch-to-batch variations in cant advance in clinical immunosuppression was the introduction potency remained problematic. "Antibody therapy" came of age in 1966 of heterologous antilymphocyte globulin (ALG) [115. with monoclonal antibodies, whose production was made feasible 162]. This was a logical extension of Gowan's demonstration of by the hybridoma technology of Kohler and Milstein [177]. OKT3. the immunosuppressive clfects of lymphoid depletion with tho­ the first-generation monoclonal antibody, was directed at all T racic duct drainage (TOO) in rats [149. 150J. In fact. Woodruff lymphocytes [178J. Subsequent antibody preparations. which in­ and Anderson showed that TOO and antilymphocyte serum clude less immunogenic humanized "hybrids." have been directed (ALS) had additivc effects [1(3). at discrete targets such as T cell subsets. adhesion molecuks. and Clinically used by Franksson and Blomstrand in 1963 to treat T cell or interleukin-2 receptors. However. when these agents arc kidney recipients in Stockholm [164J, TOO is an approach that used. the "induction" strategy has been essentially tht: same as rcsurfaced periodically during the next two decades (summarized with the original crude ALG. in [165]). Conditioning with TOO prior to transplantation clearly reduccd the frequency and vigor of kidney rejection. but 30 days (Vc/Op/lOsp/w/1lide. Although the experience during this middle of pretrcatment was required in humans [165. 166J compared to cra, defined by the first triple-drug regimen. demonstrated the the 5 days in Gowan's rats [149. 150J. However. the inconve­ feasibility of transplanting the vital extrarenal organs. it also nience. complexity. and expense of TOO precluded widespread indicated that further progress would require better baseline im­ usc [H16J. For the same reasons. total lymphoid irradiation (TLI) munosuppression. Substitution of the alkylating agent cyclophos­ [1671. which also was an clfcctive mt:ans of lymphoid depletion but phamide for azathioprine was such an cti'ort [1131. The character· with the disadvantage of not being quickly reversible. did not have istic cycle of immunologic confrontation and resolution leading to a lasting impact on clinical transplantation [I M\. 1(9). graft acceptance was no different with this drug than with azathio­ In contrast. ALG was a major lkvelopment for two rt:asons. prine-based therapy. When the results with kidney and liver trans­ First. it was a critical factor in the emergence of extrarenal organ plantation were almost identical to those using azathioprine but at transplantation. Second. it was a prototype drug from which nu­ a higher price of complications. the trials were discontinued I 1 141. merolls variations evolved. The concept of mitigating cellular Although cyclophosphamide therapy became a footnote in the immunity with heterologous antibodies had been proposed by Ilya history of organ transplantation. it continued to playa role in Metchlllkotl at the end of the nineteenth century [170J and was bone marrow transplantation. revitalized by Inderbitzen [171 J and Waksman et al. [InJ before Woodrutf and Anderson [163J. Levey and Medawar [173J. Mo­ (\·c/ospOrilll'. Another decade would pass hefore the grt:ater po­ naco. Wood. and Russell [174. 1751. and other surgeons recog­ tency of eyc\osporine would make transplantation of the liver and nized its potential role in clinical transplantation. other cadaveric organs (including the kidney) a reliable service. I !

768 World J. Surg. Vol. 24. No.7. July 2000

Cyclosporine. an extract from the fungi Cylindrocarpon lucidWll Table 5. Nonimmunologic profile. and Trichodenna polysporum. was discovered by Dreyfuss et al. Tacrolimus [179J and characterized biochemically by Ruegger et al. [180J and Factor (FK 506) Cyclosporin A Petcher et aL [181]. It was shown to be immunosuppressive by Nephrotoxicity ++,/ ++ Borel et al. [182-184] with multiple test systems including skin Neurotoxicity + + allotransplantation in mice. rats. and guinea pigs. Oiabetogenicity + + The drug depressed humoral and cellular immunity and had a Growth effects preferential and quickly reversible action against T lymphocytes. Hirsutism () +++ Unlike azathioprine and cyclophosphamide. these effects were not Gingival hyperplasia 0 ++ Facial brutalization 0 + accompanied by bone marrow depression or other prohibitive Hepatotrophic effects ++++ +++ organ toxicity. The ability of cyclosporine to prevent or delay Gynecomastia 0 + rejection of the heart, kidney, liver. or pancreas was promptly Other metabolic effects shown in rats, rabbits. dogs, and pigs by Kostakis et al. [185J. Cholesterol increase if ++ U ric acid increase +~ ++ Caine [186-188]. and Green and Allison [189] and their associ­ ates. There was no hint in these preclinical studies that nephro­ Reprinted from Starzl et al. [214]. copyright 19(H. with permission toxicity would be the dose-limiting factor in human trials. from Elsevier Science. +: best: + + + +: worst (all dose-related). The toxicity profile of cyclosporine became evident in Calne's "Less hypertension. initial evaluation of cyclosporine in human recipients of 32 kid­ hOespite this observation in humans [161] Van Thiel observed an neys. 2 pancreases. and 2 livers reported during 1978-1979 [190. increase in cholesterol synthesis and serum concentration in rats (personal 191]. The ability of the drug to prevent rejection. alone or in communication. August 1. 1990). combination with myelotoxic drugs. exceeded anything previously seen. However. the requisite overdosage caused multiple serious side effects: nephrotoxicity, neurotoxicity, diabetogenicity. a 10% The effective use of both cyclosporine and tacrolimus required incidence of B cell lymphoma. and cosmetic changes (gingival the same pattern recognition and therapeutic response that have hyperplasia, facial brutalization. and hirsutism). guided organ transplantation since its inception (Table 4). The When cyclosporine in lower doses was combined with pred­ dose ceilings of the four widely used baseline immunosuppres­ nisone in the treatment algorithm shown in Table 4, the prognosis sants were imposed by toxicity: myelotoxicity for azathioprine and of cadaver kidney recipients was improved [192]. and transplan­ cyclophosphamide and the more complex side effects shown in tation of the liver [193]. heart [194, 195]. and lungs [196] was Table 5 for cyclosporine and tacrolimus. The dose floors were brought to the level of a practical clinical service. Recapitulating revealed by the breakthrough of rejection. Because none of the the aborted avalanche of 1967, many new extrarenal programs four drugs could be used alone. they had to be incorporated into appeared. joining the five extant liver centers [Denver (from "cocktails" in which the requisite doses of the individual drug 1963). Cambridge (1968), Hannover (1972), Paris (1974), Gro­ constituents were determined on a case-to-case basis by trial and ningen (1977) I and the single remaining heart program [Stanford error. Dose-maneuverable prednisone has remained a constant (from 1(68)). This time, most of the programs flourished. for 36 years, but steroid dependence declined with the more potent baseline agents. Tacrolimlls. Cyclosporine was the unchallenged baseline immu­ The lead organ for azathioprine was the kidney. The develop­ nosuppressant for all varieties of transplantation until it was mental responsibility for cyclosporine was shared by the kidney shown in 1989 that intractably rejecting liver allografts could be and liver. and the liver bore the principal burden for tacrolimus regularly rescued by replacing cyclosporine with tacrolimus [1(7), [197,205.207,209-213]. Progress with one kind of organ allograft an extract of Streptomvces tsukabaensis discovered by Kino and inevitably meant progress for all. Thus survival of each kind of Goto et al. [198J. Tacrolimus was tested initially in a rat cardiac organ graft rose in the same three distinct Il!aps between 1962 and transplant model by Ochiai et al. [199) and soon thereafter by 1998 (Fig. 5). With tacrolimus. the intestine was no longer a Murase et al. in rats [200. 201) and by Todo et al. in dogs [202. "forbidden" organ [214-216]. 203] and subhuman primates [203. 204]. In addition to numerous confirmatory reports of its ability to Ripple Elfect rescue about 75% of intractably rejecting human liver allografts [205]. tacrolimus could salvage an equal proportion of rejecting Orgall Procllremelll alld Prcsen'ati0l1 hearts. kidneys. and other organs [2(6). [n virtually all such caSl!s. a switch back to cyclosporine was never made. Consequently. The sudden arrival of clinical kidney transplantation during 1%2- clinical trials using tacrolimus primarily Wl!rl! begun [206-2081. 1963 was so unexpected that littk collateral research or other By early 1990 more than 150 liver. kidnl!y. hl!art. and heart-lung formal preparation had been made to preserve organs. Although recipients had been treated from the time of transplantation with kidneys were successfully transplantl!d in the pioneer identical immunosuppression based on tacrolimus rather than cyclosporine twin cases despite protracted periods of warm ischemia. thl! mat­ [209]. It was learned from this experience that the three major uration of clinical transplantation could nO! procel!d without ef­ side effects of the drug (nephrotoxicity. neurotoxicity. diabetoge­ fective organ conservation. This was accomplishl!d at first with nicity) were comparable to those of cyclosporine. Hypertension total body hypothermia of living voluntl!er kidney donors [217] and hyperlipidemia were less common than in historical CYclo­ using methods dl!velopl!d by cardiac surgeons for open heart sporinl! controls. The cosmetic l!tfects of eyclosporinl! were not operations [218]. In thl! experimental lahoratorv. Lillehei et al. seen (Table 5). [41l] simply immersed the exclsl!d intestlnl! in iCl!d saline before its Starzl: History of Clinical Transplantation 769

100

-::!2. 0 80 ~ \ .:;;> 60

~ ::J • AZA (n=168) (j) 40 • eYA (n=1835) C • TAe (n=1391) Q) ca 20 a.. 0 0 1 2 3 4 5 Time after Transplantation (years)

100 • AZA (n=190) • eYA (n,,2416) -::!2. 80 0 • TAG (n=1582)

~ 60 > ~

c75 40 Fig. 6. Technique of extracorporeal perfusion with a heart-lung machine -;- described by Marchioro et al. [2201. Catheters are inserted via the femoral ~ 20 vessels into the aorta and vena cava as soon as possible after death. The (!) extracorporeal circuit is primed with a glucose or electrolyte solution to which procaine and heparin are added. The cadaver is thus anticoagulated o +-----r----r----...... ---....,.------. with the first surge of the pump. Temperature control is provided by the o 1 2 3 4 5 heart exchanger. Cross-damping the thoracic aorta limits perfusion to the Time after Transplantation (years) lower part of the body. (From Starzl [2(lJl. with permission.)

Fig. 5. Three eras of orthotopil: liver transplantation at the Universities of Colorado (1lJ63-llJXO) and Pittsburgh «(lJXI-IlJ93). dt.:fined by azathio­ prine-. cvclosporine-. and FK 506 (tacrolimus)-based immune suppres­ the simpler core cooling of cadavers with cold electrolyte solutions sion. The same stepwise improvement was seen with all organs. Top. infused into the distal aorta. Patient survival. Bottom. Graft survival. The rate here was about 10% lowt!r than that for patient survival in both tht! cyclosporine (llJXO-IlJX9) Organ ProclIremellt. Until 1981 transplantation of the extrarenal and tacrolimus eras (19X9-IYlJ3) because of effective retransplantation. an option that did not exist previously. AZA: azathioprine: CYA: cyc!ospor­ organs was an unusual event. By late 1981. however. it had he­ int!: TAC: tacrolimus. come obvious that liver and thoracic organ transplant proceuures were going to he widely used. A method of multiple organ pro­ curement was required by which the kidneys. liver. heart. and lungs or various combinations of these organs could he removed autotransplantation. a method also used by Shumway when de­ without jeopardizing any of the individual organs. "Flexible tech­ veloping experimental and clinical heart and heart-lung transplan­ niques" were developed [223. 2241 that were quickly adopted tation [45-471. Thus the principle of hypothermia was understood worldwide. With these methods all organs to be transplanted are at an early time. although not efficiently applied. cooled in situ. rapidly removed in a bloodless field. and dissected The first major innovation in hypothermia was in the labora­ on a back table. The sharing of organs from a common donor hy tory. when canine liver allografts Were cooled by infusion of recipient teams from widely separated centers became routine by chilled fluids into the vascular bed of hepatic allografts via the the mid-llJ80s. portal vein [431. Before this time. dogs after liver transplantation was almost never survived. whereas afterward sUCCess hecame Er Vim Pel1ilsicJIl. Extension of the safe period after initial cool­ routine. In a logical extension to clinical kidney transplantation. ing has followed one of two prototype strategies. developed with the practice was introduced in 1963 of infusing chilled lactated kidneys or livers and applied secondarily to other organs. One Ringer's or low-molecular-weight uextran solutions into the rcnal approach that was extensively evaluated by Alexis Carrel and the artery 01 kidney grafts immediately after their removal [2191. aviator Charles A. Lindberg was to simulate normal physiologic Todav. intravascular woling is the first step in the preservation conditions with ex vivo pcrfusion techniques [2251. This concept llf all whole-organ grafts. For cadaver uonllrs. this is most often was modified hy Ackerman and Barnard [2261. who proviueu the done in situ hy some variant of the technique descrihed hy Mar­ isolated organs with a continuous low-tlow renal arterial circula­ chioro et al. 12201 (Fig. 0). This methou for the continuous hypo­ tion using a perfusate primed with hlood and oxygenated within a thermic perfusion of cauaveric livers anu kiuneys was useu clini­ hyperharic oxygen chamber. This tcehnique also permittcu goou cally long before the accepwnce of brain death. Ackerman anu preservation of hepatic allografts for as long as a Jay 12271. Snell 122 II anu Mcrkel. Jonasson. allu Bergan (2221 popularized However. the complexitv of thc me thou precluueu its general 1I,e. 770 World J. Surg. Vol. 24, No.7, July 2000

Elimination of the hemoglobin and hyperbaric chamber com­ other molecules was delineated with insulin-like hepatotrophic ponents by Belzer et al. [228] resulted in satisfactory kidney properties [241\]. Eventually the gene was discovered that ex­ preservation for up to 2 to 3 days. The asanguineous perfusion presses one of them (augmenter of liver regeneration) [249-251]. technique eventually was abandoned in most kidney transplant The hepatotrophic factors. most of which are cytokines [e.g., centers when it was learned that the quality of 2-day preservation hepatocyte growth factors (HGF) J. rcgulate liver size, structure. was no better than with the simpler "slush" methods (see below). regeneration. and metabolic homeostasis. Nevertheless, it is expected that refinement of perfusion technol­ Studies of hepatotrophic physiology led directly or indirectly to ogy will someday permit true organ banking. liver rcplacement for cure of more than two dozen hepatic-based inborn errors of metabolism [252J, including familial hypercholes­ "Slush" Preservation. With the so-called static methods, fluids of terolemia [73, 74J. The role of hepatic transplantation in first differing osmotic, oncotic, and electrolyte composition are infused suggesting, and then proving, that the liver governs cholesterol into the allograft before placing it in a refrigerated container [229, metabolism has been described elsewhere [73, 74, 252,253]. Elu­ 230]. The solution described by Collins, Bravo-Shugarman, and cidation of the cellular and molecular mechanisms was rewarded Terasaki [229] (which resembles intracellular electrolyte concen­ by bestowal of the 1985 Nobel Prize to Brown and Goldstein trations) or modifications of it were used for almost two decades. (Table 2). Renal allograft preservation was feasible for 1 to 2 days, long enough to allow tissue matching and sharing of organs over a wide Immunologic Screening geographic area. Experiments with hepatic allografts by Benichou et aJ. [231] using the Collins-Terasaki solution and by Wall et al. The importance of the genetically determined major histocom­ [232] with the plasma-like Schalm solution led directly to liver patibility complex (MHC) in determining the immune response to sharing among cities but with a time limitation of only 6 to 8 allografts was evident from investigations by George Snell in hours. inbred mice [254], which in turn derived from the work of Peter Introduction of the University of Wisconsin (UW) solution to Gorer [255]. However, the information was not clinically applica­ liver transplantation by Belzer, Jamieson, and KalayogJu [233, ble. Thus immunologic screening of donors and recipients was not 234] was the first major development in static preservation since done during the volatile developmental period of 1959-1963 [1]. the Collins-Terasaki solution [235]. The superiority of the UW The possibility of tissue matching did not begin to emerge until solution for preservation of the kidney and other organs was the discovery by Dausset of the first human leukocyte antigen promptly demonstrated in experimental models and confirmed in (HLA) in 1958 [256] and the discovery that same year by Van clinical trials [236-241]. The UW preservation doubled or tripled Rood et al. [257] of anti-leukocyte antibodies (soon shown to be the time of safe preservation of the various allografts. making HLA-directed) in the sera of pregnant women. The report in 1964 national and international sharing of most organs an economic by Terasaki and McClelland [258] of the microcytotoxicity test. and practical objective. with which HLA antigens could be detected serologically in minute quantities of sera. was a critical development in moving Life Sciences forward with the classification of the antigens.

While occupying its own unique niche, transplantation has drawn Crossmatch Principle from and in turn enriched all of the other basic and clinical scientific disciplines. Aside from changing the philosophy by As it turned out. the greatest impact of pretransplant tissue which organ-defined specialties of surgery and medicine arc prac­ matching has been the prevention of hyperacute rejection by tices. transplantation grew parallel with and contributed in a observing ABO compatibility guidelines and routine use of the major way to advances in immunology, pharmacology, oncology cytotoxicity crossmatch. (e.g., the role of tumor immune surveillance [158.242]), infectious disease. intensive care, and anesthesiology. Study of each of the ABO Compatibilitv. Hyperacute rejection was first observed more allografts has yielded an organ-specific harvest of special infor­ than 30 years ago when ABO-mismatched renal allografts were mation. Examples include a better understanding of diabetes transplanted into patients who had preformed anti-graft ABO mellitus with pancreas transplantation and the effects of denerva­ isoagglutinins [54. 259J. After kidneys were lost on the operating tion on cardiopulmonary function with heart and lung transplan­ table. arteriograms of the infarcted organs showed nonfilling of tation. the small vessels. correlating histopathologically with widespread The liver became the key organ in unmasking the secrets of thrombotic occlusion of the microvasculature. It was concluded acquired tolerance because of its large content of immunocom­ that high-affinity isoagglutinins in the recipient serum had bound petent leukocytes (see earlier and Allograft Acceptance versus to A or B antigens in the graft vessels and parenchymal cells. This Acquired Tolerance. below). In addition. the functional complex­ was consistent with the rapid changes in recipient isoagglutinin ity of the liver and its metabolic interactions with other abdominal titers that followed organ revascularization. The guidelines for­ viscera have made hepatic transplantation a "mother lode" for mulated from this experience [54. 259] were designed to avoid physiologic studies [243]. such antibody confrontations (Table I). During the course of determining the optimal revascularization The ABO rules also apply to heart. liver. and other organ of auxiliary livers transplanted to ectopic sites or to the normal transplantation. As was originally observed in 11)63 with ABO­ location [43. 244. 245], it was found that endogenous insulin is a mismatched kidneys. however. [54. 259]. not all organs placed in liver growth factor [246. 247]. the first such hepalOtrophic factor the hostile environment of anti-graft isoagglutinins meet the same to be identified. Using transplantation-derived models. a family of fate. In fact. the longest continuously functioning renal allograft in Starzl: History of Clinical Transplantation 771

Tissue Matching Historically, it was predicted that tissue matching would have to be perfected if long-term engraftment of tissues and organs was to succeed with any degree of reliability and predictability. The prophecy was immediately fulfilled with bone marrow transplan­ tation. in which anything less than a perfect or near-perfect match Immune between the donor and recipient resulted in GVHD or rejection Reaction of the graft [27-30]. When similar expectations were not met in studies by Terasaki in kidney transplant recipients. the results initially were treated as a scientific scandal [278, 279]. When he later was proved to have been correct, Terasaki emerged as the Time after Transplantation father of HLA matching and as an enduring symbol of integrity. Terasaki's investigations began with a retrospective study of the Fig. 7. Contemporaneous host-versus-graft (HVG) and graft-versus-host influence of HLA matching on the quality of outcome of patients (GVH) reactions in the two-way paradigm of transplantation immunology. Following the initial interaction. the maintenance of nonreactivity of each with long-surviving kidney allografts [280], followed by a prospec­ leukocyte population to the other is seen as a predominantly low grade tive trial in live donor kidney recipients treated with azathioprine stimulatory state that may wax and wane. rather than a deletional one. and prednisone. with or without adjunct ALG [281]. Consistent with the results in the classic skin graft investigations in nonim­ munosuppressed healthy volunteers by Rapaport and Dausset the world [109] is a B+ kidney donated to a then 38-year-old A + [282-284], HLA-matched allografts had the best survival and male recipient by his younger sister on January 31, 1963. In function. the least dependence on maintenance prednisone. and addition, it was learned at an early time that the liver is more the fewest histopathologic abnormalities in routine 2-year post­ resistant to antibody attack than other organs [260]. operative biopsy specimens [285]. Unexpectedly, however. no cu­ In histocompatibility studies in which human volunteers were mulative adverse effect of mismatching in the kidney recipients sensitized with purified A and B blood group antigens, causing could be identified. variably increased titers of isoagglutinins. Rapaport et al. [261] The equally imprecise prognostic discrimination of HLA showed accelerated or hyperacute (white graft) rejection of ABO­ matching in cadaver kidney transplant cases also was first recog­ incompatible skin grafts transplanted to recipients with high titers. nized by Terasaki (with Mickey et al. [286)) and has been evident This completed the circle of evidence indicting anti-graft antibod­ in analyses up to the present time. With the large sample sizes in ies as the precipitating cause of hyperacute organ rejection. United Network for Organ Sharing (UNOS) and European data­ bases, virtually every comparison of the different levels of mis­ With Non-ABO Antibodies. In 1965 hyperacute rejection of a matching showed statistical significance. However. the absence of kidney by an ABO-compatible recipient was reported for the first a large or consistent matching effect unless there is a perfect or time by Terasaki et al. [262]. Terasaki's observation that the near-perfect match has always been the same. In a recent study of serum of the recipient of a live donor kidney contained preformed more than 30.000 UNOS patients for whom optimal matches had anti-graft Iymphocytotoxic antibodies was promptly confirmed in been sought prospectively, approximately 85% of the cascs were similar cases by Kissmeyer-Nielsen et al. [263) and others [264. in the two- to five-HLA mismatch spectrum. where I-year survival 2(5). Evidence of a cause-and-effect relation in the single first case was clustered within 3%. Subsequent half-life projections there­ was so clear that Terasaki recommended and immediatelv intro­ after were in the narrow spread of 9 to 11 years [287]. duced his now universally applied Iymphocytotoxic cro~smatch Terasaki's conclusions nearly three decades ago hreathed life test [262. 2(6). into the still struggling field of liver, heart. and lung transplanta­ It has been shown in presensitized animals and humans that tion. It was a relief to know that the selection of donors with antibodies. clotting factors, and formed hlood elements were random tissue matching would not result in an intolerable penalty. rapidly cleared by the hyperacutely rejecting grafts [267, 2(8). A quarter of a century passed hefore it could be explained whv Local fibrinolysis from the renal vein also was a consistent finding; HLA matching was critical for bone marrow. but not orga~. and in exceptional cases there were systemic coagulopathies with transplantation (see the section that follows). disseminated intravascular coagulation (DIC) [269. 270). The findings are comparable to those seen with the Arthus reaction. Allograft Acceptance versus Acquired Tolerance inverse anaphylaxis. generalized Shwartzman reaction. and other models of innate immunity [265. 269. 270). During the Festschrift at Harvard honoring Paul Russell's retire­ Non-HLA antibodies such as anti-vascular endothelial cell an­ ment in late November 1990. Norman Shumway told me and tibodies also have been associatcd with hyperacute or accelerated Leslie Brent about his textbook on thoracic transplantatIOn for rejection [271. 272). The vulnerabilitv of extrarenal organs to this which he wanted two chapters: one explaining the classic immu­ kind of rejection was ultimately demonstrated exp~rimentally nologic tolerance exemplified by bone marrow transplantation [273-275) and c1inicallv. Although the liver was the most antibodv and the other defining the presumably different mechanisms of resistant [260]. it too ':;"as placed at increased risk by the presen'­ whole organ allograft acceptance. On learning that I thought the sitized state [276). Hyperacute rejection also has been docu­ two were the same in principle. Shumway assigned me the task of mented in a small number of human organ recipients in the defending this opinion [288]. absence of detectable antibodies [265. 277). Evidence was obtained first from investigation of long-surviving World J. Surg. Vol. 24. No.7, July 2000 772

One-Way Paradigm (Organ) One-Way Paradigm (Bone Marrow) t O~ GVH 01/: CJ1 o r:L ~ o , ~ Delensel ... Graft ~ ...... ©~ .••. 0/ ~y @.l0 :.; .... : ..... !. ~ .,uu,." .... ·.,."',· ... "••• , Cytonl.,.on , •. ,., ","t •• L HVG (RejectiOn)--I ".Jaftt_ Ott.pm,. F' HybllCi Fig. 8. Top panels. One-way Two-Way Paradigm (Organ) Two-Way Paradigm (Bone Marrow) paradigm in which transplantation is conceiv~d as involving a 'mmunosuppresslon GVH unidirectional immune reaction: Mutua' Natural . 't'-. I ~ Immuno·tp.... 'on host-versus-graft (HVG) with GYH + whol~ organs (left) and graft­ I M",,,I' Halural .: .' :avO. O ••t" ••• ,•• ~ '5' . .o..@ versus-host (GVH) with bone " ~ Ie -.°: 0 @ ------,...... ::· marrow or other Iymphopoi~tic . . • :0°0 @', ~ @ ~ . o.·0· •••: transplants (right). Bottom .... . 0 .• O\@'@ .• :.'. 00 •• @ ~ • •• 0 •• • @t;f. ·0.'.~ :~. ~~." r ~,..\ @ panels. Two-way paradigm in $ • 0° . " \", VLCt • .~:~o @ ~.. ~. ~:. ~ . . @l. • '·0'·.o~ o. 0 I @c .. which transplantation is se~n as a • • III @t@! bidirectional and mutuallv .~: Un.nlred 80n. ~ 1 canceling immune reaction that is NOI O""'e ! @}-~@ " Marrow v.to/Suppr •• ,or Celli o.t.n:'~!~'U~:CiPI.nt 0 ...", ..... G,all v.to/Supp..... , Cene @.! Unconditioned Cytoiline ProWe Ch.ng •• predominantly HVG with whole Enhlncmg Antibodi.. CyIO.bl.tIOft Ca-'.,'. drug') eY'OIl.N Prom. Chan... AecitMent organ grafts (left) and l"NnCII'!, Anltbod~. I L HVG predominantly GVH with bon~ HVG (Rejection) ~ marrow grafts (right).

Owen Martinez/Good 5l Maintenance (3) Freemartin Cattle Parabiosis Organ Tx c (1945) (1960) (1992) I a: 4 •• , ...... ---- <1l c ...... (2 t) :J E §

Leucocyte Depletion (4)

Billingham/Brent Slavin/Strober (1977) Medawar IIdstad/Sachs (1984) (1953) Thomas (1987) Time Fig. 9. Continuum of chim~rism from th~ observations of Ow~n in fr~~­ Fig. 10. Four t:vents that occur in dose !I.:mpmal approximation when martin cattle to the di,cov~ry in 1992 of microchim~rism in organ recip­ there is successful organ engraftm~nt. Top. DllUhk :.Jeutt.: clonal ~xhaus­ Ients. tion (\, 2) and subsequ~nt maintenanc~ donal exhaustion (.\). Bottom. loss of organ immunogenicity due to dt.:plt.:tion of tht.: graft's passengt.:r I~ukocytes (4).

human liver. kidney. and other organ recipients [31. 33.11\9-291 J and those following bone marrow transpl

IR»V IR«V IR~V V Unopposed (Exhaustion I deletion (Immunologically of immune response) Ignored) • W I • 0 g ::J ~i ••••• t- •• Z •• C) -a;:~i • Stable • Carrier c( • i1! § • '. Stlte Warts. Papillomas ~ ...... • in keralinocytes ~E •.... Chronic tnfection >5 .....

Transplant Acute graft rejection Stable graft Chronic graft rejection Leukocyte depletion: Analogue: (or GVHD) acceptance ( orGVHD) of allograft of recipient (cytoablation) TIM E Fig. II. Variable outcomes after infection with widl!lv disseminated non· tal axis denotes time. and the vertical axis shows the viral load (V. solid cytopathic viruses (or other microorganisms) and an~logies (helow indi­ line). and the host immune response (IR. dashed line). vidual graphs) to organ and bone marrow transplantation. The horizon-

(i.e., the host was the defenseless target) was the conventional the graft hy host cells. The result is widespread antigen-specific view of bone marrow transplantation (Fig. ~, top right). Only two immune activation of the coexisting donor and recipient cells, pioneer workers raised objections to the definition of transplan­ each by the other. which proceeds in successful cases to variable tation immunology in terms of a unidirectional immune reaction. reciprocal clonal exhaustion and then deletion (Fig. 7). In 1960-1901, Simonsen (141) and then Michie. Woodruff. and Engraftment under clinical circumstances requires an umbrella Zeiss [296) postulated that the two populations of immune cells in of immunosuppression to prevent one ccll population from de­ neonatally tolerant mice managed to coexist in a stable state hy stroying the other: but in some experimental models it occurs becoming mutually nonreactive while retaining the ability to func­ spontaneously (e.g .. after pig liver transplantation and in many tion collahoratively (i.e .. in a joint immune response to infection). rodent models). The "nullification" of thl! two arms explains thc Although this heretical suggestion resembled the concept sum­ poor prognostic value of HLA matching for organ wrsus bone marized in Figures 7 to II. the Simonsen-Woodrutr hypothesis marrow transplantation (Tahle 6) and the low incidence of was recanted in 1902 [2(7), ostensibly hecause no experimental GVHD following the cngraftment in noncytoahlated recipients of support could he found for it. More importantly. however. it had immunologically active organs, such as the intestine and liver. heen advanced in a nonreceptive climate in which "group think" In addition to inducing clonal activation and exhaustion hy had already turned in a different direction. For the next 30 vears trafficking to host lymphoid organs, donor leukocytes that survive transplantation immunity and tolerance were conceived as prod­ the initial dcstructive immunc reaction migrate secondarily to ucts of unidirectional immune reactions of the kind that could he non lymphoid areas. where thev do not generate an immune rc­ studied in vitro hy one-way mixed lymphocyte culture techniques sponse ("immune indifference"). From hcre they may "lcak" pe­ descrihed hy Bain and Lowenstein [29X) and Bach and Hirschhorn riodically to the host lymphoid organs and maintain clonal ex­ [2(9). haustion, With clonal cxhaustion/delction and Immun.: After chimerism was discovered in organ recipients in 1992- indiffcrcnce in combination, hoth of which arc rcgulatcd hy the 1993 [32-34) it was recognized that the interaction of the coexist­ migration and localization of the antigen (34), the four interrl!­ ing donor and recipient leukocyte populations was the common lated events shown in Figure 10 must occur close together to have factor that underlay both the "acccptancc" induccd by whole organ engraftment: douhlc acute clonal nhaustion. maintenancc organ allografts (Fig. S. hottom left) and thc tolerancc induced clonal exhaustion (which frequently waxes and wanes), and loss of with bonc marrow (Fig. S. hottom right). This context closed the graft immul1ogl!tlieity as the organ is depleted of its passenger 30-year intellectual gap between the fields of organ and bone Icukocytes. marrow transplantation. Organ-associated chimerism then could hI! idl!ntitied in a continuum of classic tolerance models [5. II. BOllI.' MlII1"Ol\" TO/('/"(/IIC1.' 167. 300-J021 beginning with the originalohservations hy Owen in frl!emartin cattlc (Fig. 9). Pretransplant cytoahlation renders the recipient susceptihlc to immune attack hy donor immune cclls (i.c .. GVHD). control of which frequently becomes the principal ohjective immllnosup­ OI1:ClI/ t.'lIgralillll'llt 01 prcssion. rathcr than the prevcntion of rejection (Tablc 11). Be­ The immunocompetent donor Icukocvtcs in organ transplantation cause complcte dcstruction of host leukocytes is not possible with dre highly immunogl!nic. multilincag.: "passengl!r lcukocytes" of conventional dllSCS 01 cytoablation [3()31, the remaining cclls stim­ hone marrow origin (including stcm and dcndritic cells) that ulate an allllrcsponse hy mature or maturing donor T cdb. Nev­ migrate preferentially to host Ivmphoid org,1I1S ,llld are replaced in ertheless. undl!r illlmunosllpprcssive treatmcnt. a weak hll~t-\"cr- 774 World J. Surg. Vol. 24, No.7. July 2000

Table 6. Differences between conventional bone marrow and organ Table 7. Effectors involved in response to cytopathic parasites and transplantation. discordant xenografts. First line of defense Bone marrow Organ Factor Interferons Recipient cytoablation" Yes No Macrophag.es MHC compatibilitv Critical Not critical yeS T cdls Principal complication GVHD Rejection Natural killer (:-.IK) cells Drug-free state Common Rare B cells Term for success Tolerance .. Acceptance .. " Nonspecific or less specific c!fcctors Complement GVHD: graft-versus-host disease: MHC: major histocompatibility Early interkukins complex. Phagocytes "All differences derive from this therapeutic step which in effect establishes an unopposed GVH reaction in the bone marrow recipient whose countervailing immune reaction is eliminated. "Also referred to as "operational tolerance." plantation (Fig. 11. third panel) or uncommonly GVHD. The conditions in the cytoablated bone marrow recipient mimic those of an infection by microorganisms (e.g .. rabies and wart viruses) sus-graft reaction mounted by these few recipient cells and a that avoid immune activation by not migrating through (or to) para lid graft-versus-host reaction mounted by the donor bone host lymphoid organs (Fig. 11. right panel) [34]. marrow cdls may eventually result in reciprocal tolerance by Because immunity and tolerance to alloantigens follow the deletion. These processes represent a mirror image of the events same rules as the response to noncytopathic microorganisms [34]. after organ transplantation (Fig. 8. bottom right). it is not possible with current transplantation practices to induce tolerance to allografts on one hand without risking unwanted Relation to Infectiolls Disease tolerance to pathogens on the other. In this context. the historical anxiety depicted in Figure 4 was correct. NoncYlOpathic Microorganisms. Early workers in transplantation [304,305] recognized the resemblance of allograft rejection to the Cytopathic Microorganisms. There is no MHC-restricted safety response against infections associated with delayed hypersensitiv­ valve for cytopathic microorganisms that are typically extracellular ity, exemplified by tuberculosis. With the demonstration of the and generate the full resources of the innate and the adaptive MHC-restricted mechanisms of adaptive infectious immunity by immune system [310, 311). An uncontrollable innate immune Doherty and Zinkernagel in 1973 [306-3()9], it became obvious response involving the effectors shown in Table 7 is provoked by that allograft rejection must be the physiologic equivalent of the discordant xenografts expressing the Gal a Gal epitope. an response to this kind of infection. Microorganisms that generate epitope that also is found on numerous cytopathic bacteria. pro­ such an adaptive immune response arc generally intracellular and tozoa, and viruses. have no or low cytopathic qualities [310]. The clinical use of such discordant animal donors requires Although M HC-restricted host cytolytic T lymphocytes recog­ changing the xenogeneic epitope to one that mimics a noncyto­ nize only infected cells. elimination of all the infected cclls could pathic protile or else eliminating the epitope [312]. Although disable or even kill the host. Consequently. mechanisms have chimpanzees and baboons do not express the Gal antigen. the evolved that can tempcr or terminate the immune response. al­ clinical xenografts transplanted from these subhuman primate lowing both host allli pathogen to survive [310. 311]. They arc the donors in 1963 [51. 52] ultimately were damaged by an uncontrol­ same two mechanisms that allow survival of allografts (i.e., clonal lable innate immune reaction. dominated by complement activa­ exhaustiorlideletion and immune inditferenee) [34]. both of which tion. Similar innate immune mechanisms were recognized during arc governed by antigen migration and localization [34. 310. 311]. the 1960s to be responsible for the hyperacute destruction of However. unlike the complex dual immune response of transplan­ ABO-incompatible allografts or allografts transplanted to presen­ tation. infectious immunity is essentially a host-versus-pathogen sitized recipients (sec earlier) [265-270]. reaction. The analogies between transplantation and an infection with Self/NOli-self Discrimination disseminated noncytopathie microorganisms can be exemplified by the common hepalitis viruses. as shown in Figure II [34. :110. Survival in a hostile environmcnt requires the ability to moullt a :I II]. The pathogen (antigen) load may rapidly increase during the protective immune response while avoiding a reaction of the so-called latent pniod but then he dramatically and efficiently immune system against self. Transplantation has succeeded he­ controlled by antigen-specific etrector T cells. which then subside cause it has not lethally eroded this capability. which dcpends (Fig. II. far left panel). The transplantation analogues arc acute ultimately on the governance of immunologic responsiveness nr irreversible I'CJection (or Intractable GVHD). Alternatively. a con­ unresponsiveness by migration and localization of antigen [34). tinuously high antigen load with an allligen-specitie immunologic Because the fetus possesses early T cell immune function [313- collapse (Fig. I I. second panel) is equivalent to unqualitied ac­ 315] the ontogenv of self/non-self discrimination during fetal de­ ceptance ()f an allogratt. velopment can be explained by the same mechanisms as aequircd 13etween these two extremes. the persistence of both the infec­ tolerance during later life. Autoimmune di ... eases then retleet tious agent and a ... trong immune response results in serious unacceptable postnatal perturbations 01 the prenatally established immullopathology (e.g .. chronic active hepatitis with HBV or localization of self antigens in nonlymphllid versus lymphoid com­ HCV infection) comp

Conclusions des changements radicaux dans la tactique therapeutique. Apres la decouverte en 1992 que les survivants a long terme avaient un The lesson described in this chapter has been learned manv times microchimerisme persistant. il a ete possible de comprendre ee before: All knowledge can be traced to its roots and ultim~tclv to qu'il y avait en commun du point de vue mecanique entre la a seed. For clinical transplantation. the historical beginning ~as transplantation d'organe et celle de la moelle osseuse. Des lors, 'Vtedawar"s recognition that rejection is an immune re;ction.-Only un principe commun d'immunologie a pu etre eIabon~ pour guider two primary roots sprang from this seed. One was the demonstra­ [,induction de fac;on systematique d'une tolerance aux tissus tion by Billingham, Brent, and Medawar in 1953 that tolerance humains. et peut-etrc eventuellement, meme aux xenogretfes. could be acquired by producing stem cell-driven hematolympho­ poietic chimerism [5]; this concept ultimately led to bone marrow transplantation in humans. The other root was the demonstration Resumen during 1962-1963 that kidney allografts could consistentlv self­ induce tolerance with the aid of immunosuppression [3~1]; all Con el desarrollo de la cirugfa de trasplantes, se descubrieron una further developments in organ transplantation derived from this serie de agentes inmunosupresores cada vez mas potentes, discovery. The assumption reached by consensus during the early mejorandose adem as los metodos de preservacion de organos y 1960s that the two roots reflected different immune mechanisms tejidos; tambien se refinaron las tecnicas de histocompatibilidad led to inadequate explanations of organ allograft acceptance and cruzada. Al mismo tiempo. se produjeron numerosas clouded the meaning of successful bone marrow transplantation. innovaciones por 10 que a la tecnica quinirgica se refiere. Todos The false assumption, which promptly became dogma, saddled estos esfuerzos han permitido que en el momento actual sea succeeding generations of scientists and clinicians with a context posible trasplantar en t!l hombre. con exita. cualquier organo asi that precluded synthesis of a clarifying central principle of immu­ como las cclulas de la mcdula ost!a. Sin embargo, cl desarrollo de nology that could be applied to all transplant. much less nontrans­ los trasplantes dependio b,isicamente de dos investigaciones plant. circumstances. After it was discovered in 1992 that organ fundamentales: la primera fue el descubrimiento, en 1953, por recipients had persistent microchimerism, it was possible to see Billingham, Brent y Medawar, de la posible induccion de un the essential commonality of organ and bone marrow transplan­ quimerismo deliberado. propiciado por la tolerancia neonatal. EI tation. to relate observations after these procedures to the im­ desarrollo de este descubrimiento permiti6, 15 alios mas tarde mune response to infectious diseases and neoplasms, and to ex­ (1968), realizar con exito el primer trasplante de medula osea. EI plain the genesis of self/non-self discrimination. segundo hito en la historia de los trasplantes fue la demostraci6n, a principios de los alios 60. que tanto en cl perro como en cl hombre, los injertos alogcnicos pucden Ilcgar a tolerarse por si Resume mismos merced a la ayuda de la inmunosuprcsi6n. Sin embargo, a finales de 1962 se pens6 erroneamcntc que estos hitos se debian La transplantation s'est dcveloppee griice des agents a a diferentes mecanismos inmunologicos. Este error no se corrigi6 immunosuppressifs de plus en plus puissants. une amelioration a hasta bien entrada la dccada de los 90. En esta revision hist6rica. des methodes de conservation des tissus et des organes, aux se resume la ingente litenitura publicada al respecto durante los progres dans I'etude de I'histocompatibilite et aux n~mbreuses 30 ultimos anos. Los progresos realizados en clinica. innovations dans les techniques chirurgicales. De par une admirablemente documentados, explican cumplidamentc 10 que combinaison de tels changements s'est ouverte la voie de grctfes no cansigue la bibliografia re"isada: la aeeptacitin de aloinjertos de pratiquement to us les organes y compris la moe lie o;seuse. en receptores predestinados a sufrir de por vida un tratamiento chez I·homme. Au plan bcaucoup plus fondamental. cependant. la inmunosupresor. hecho que originani cambios fundamentalcs en reussite de la transplantation a etc lice deux points a las pautas terapcuticas. AI descubrirse en 19l)2, que en reccptores determinants. Le premier a ete la reconnaissance par Billingham, de un organa trasplantado. con larga sllpervivencia, aparece un Brent et Medawar en 1953 qu'il etait possible d'induire microquimerismo persistente, fue posible clariticar los dCliberement une tolerance neonatale chimerique. Cette mecanismos comunes en los trasplantes de ()rganos y de m':dula decouverte a permis, pendant les 15 'Ins suivants, de progresser osea. As!. un clariticador principio fundamental de illmunologia rapidement vcrs la premiere greffe de moclle osseuse qui a eu lieu pudo sintctizarse, por el que se rigen los esfuerzos para indu:ir chez I'homme en 1968. Le deuxicme point a etc la demonstration una tolerancia sistem:itiea de los te.lidos hutllanos y tal vez. en au debut des annees 1960 que les allogretfes d'organes d'origine liitimo termino. de los xenoinjertos. humaine et canine pouvaient indui;e par ell~s-mcmes -une tolerance il ['aide des medicaments immunosuppresscurs. A la tin de LlIlllee 1%2, .:ependant. on a wnclu. il tort, que lcs deux Aekn()wled~ments points en questions relevaient de mecanismes immuns ditfCrents. Cette erreur n'a pu etre corrigec que pendant les annees 19l)O. This study was supported in part by research grants from the Dans cet article sur I'historique des transplantations. on resume la Veterans Administration and Project Grant DK-2lJ%1 from the vaste litterature qui en est nee pendant cette periode de 30 ans. National Institutes of Health, Bethesda. MD. Bit!n que les progres empiriqucs soicnt admirablement bien documentes dans Ie domaine de la transplantation clinique, cette mcme richcsse littcraire n'a pu expliquer pourquoi line grctfe References d'organc allogeniquc reussit. Par manque d'explication precise, I. History of HLA: T~n R~coll,xtil)ns. T .:r~lsaki. 1'.1.. .:Jiwr. L", An· mantes rece"eurs de gretIc d'organe ont etc condamnes ;\ une gd.:s. UCLA TisSll': T\rin~ L.ahoratorv. 1'Nil. rr. 1-2hlJ immunosuppression il vic ct ce manque d'information a empcche , Historv ot Transriantatlllll: Thirt\'·Fi\t: R.:wllections. T.:rasakl. 1'.1.. 776 World J. Surg. Vol. 24. No.7, July 2000

t:ditor. Los Angt:les. UCLA Tissue Typing Laboratory. 1990. pp. 30. Thomas. LD.: Allogeneic marrow grafting: a story of man and dog. 1-704 In: History of Tran~plantation: Thirty-Five Recollections. Terasaki. 3. Gibson. T .. \1edawar. P.B.: The fate of skin homografts in man. 1. P.1.. editor. Lu, Angeles. UCLA Tissue Typing Laboratory. 1991. pp. Anat. 77:299. 19·B ~ 379-:193 ~" Medawar. P.B.: The behavior and fate of skin autografts and skin 31. Starzl. T.E .. Marchioro. T.L Waddell. W. R.: The reversal of rejec­ homografts in rabbits. 1. Anat. 78:170. 1944 ~ tion in human renal homografts with subsequent development of 5. Billingham. R.E.. Brent. L.. Medawar. P.B.: "Actively acquired tol­ homograit tolerance. Surg. Gvnecol. Obstet. J 17:385. I '!O3 crance" of foreign cells. Nature 172:003. 1953 32. Starzl~ TE.. Demetns. A.J .. ' Murase. N .. lIdstad. S .. Ricordi. c.. o. Traub. E.: Persistence of lymphocytic choriomeningitis virus in im­ Trucco. M.: Cell migration. chimerism. and graft acceptance. Lancet mune animals and its relation to immunity. 1. Exp. Med. 63:847. 1930 339:1579. 19'J:! 7. Murphy. 1.B.: Transplantability of malignant tumors to the embryos 33. Starzl. T.E .. Demetris. AJ.. Trueco. M .. !\turase, N .. Ricordi. C. of a foreign species. l.A.M.A 59:874. 1912 I1dstad. S .. Ramos. H .. Todo. S .. Tzakis. A. Fung. 1.1.. Nalesnik. M .. 8. Murphy. 1.B.: Factors of resistance to heteroplastic tissue-graftings. Zeevi. A .. Rudert. W.A .. Kocova. M.: Cell migration and chimerism III. Studies in tissue specificity. 1. Exp. Med. 19:513. 1914 after whole-organ transplantation: the basis of graft acceptance. 9. Billingham. R .. Brent. L.. Medawar. P.: Quantitative studies on tissue Hepatology 17: 1127. 199:1 transplantation immunity. III. Actively acquired tolerance. Philos. 34. Starzl. T.E .. Zinkernagel. R.M.: Antigen localization and migration Trans_ R. Soc. Lond. (BioI.) 239:357, 1956 in immunity and tolerance. N. Engl. 1. Med. 339:1905. 1998 10. Hasek. M.: Vegetavni hyhridisace zivocichu spojenim krevnich 35. Starzl. T.E.: Demetris. A.1.: Transplantation milestones: viewed with obehu v embrvonalnim vyvojhi. Cesk. BioI. 2:265. 195:1 one- and two-way paradigms of tolerance. 1.AM.A. 273:876. 1995 II. Owen. R.D.: Immunogt:netic consequences of vascular anastomost:s 36. Carrel. A: The operative technique for vascular anastomoses and between bovine twins. Science 102:400. 1945 transplantation of viscera. Lyon Med. 98:H5'1. 1902 12. Anderson. D .. Billingham. R.E .. Lampkin. G.H .. Medawar. P.B.: The 37. Woodruff. M.F.A: The Transplantation of Tissues and Organs. use of skin grafting to distinl!uish between monozygotic and dizygotic Springfield. IL Charles C Thomas. 1960. pp. 1-777 twins in cattle. H~reditv 5:379. 1951 . ~ . ~ 38. Simonsen. M.: Biological incompatibility in kidney transplantation in 13. Starzl. TE .. Butz. G.W.. lr.: Surgical physiology of the transplanta­ dogs. II. Serological investlgations. Acta Pathol. Microbiol. Scand. tion of tissues and organs. Surg. Clin. North. Am. -12:55. 1'162 32:36. 1'153 14. Burnet. F.M .. F.:nnt:;. F.: Th; Production of Antibodies. 2nd ed .. 39. Dempster. W.1.: Kidney homotransplantation. Br. 1. Surg. -10:447. Melbourne. Macmillan. 1949. pp. 1-142 1953 15. Billingham. R .. Brent. L.: A simple method for inducing tolerance of 40. Lillehei. R.C.. Goott. B .. Miller. F.B.: The physiologic response of skin homografts in mice. Trans. Bull. -1:67. 1957 the small howelof the dog to ischemia including prolonged in vitro 16. Billingham: R .. Brent. L.: Quantitative studies on transplantation preservation of the howe I with successful replacement and survival. immunity. IV. Induction of tolerance in newborn mice and studies on Ann. Surg. 150:543. 1959 the phenomenon of runt disease. Philos. Trans. R. Soc. Lond. (BioI.) 41. Moore. F.D .. Smith. L.L.. Burnap. T.K.. Dallenbach. F.D .. Dammin. 2-12:4:1'). 1959 G.1 .. Gruher. U.F.. Shoemaker. W.c.. Steenburg. R.W .. Ball. M.R.. 17. Simonsen. M.: The impact on the developing embryo and newborn Belko. 1.S.: One-stage homotransplantation of the liver following animal of adult homologous cells. Acta Pathol. Mierobiol. Scand. total hepatectomy in dogs. Transplant. Bull. 6: 103. 1959 -IO:4HO. IlJ.'i7 ~ 42. Moore. F.D .. Wheeler. H.B .. Demissianos. H.V .. Smith. L.L.. Bal­ IX. Brent. L.: ..\ Hi,tory of Transplantation Immunology. San Diego. ankura. 0 .. Abel. K .. Greenberg. 1.B .. Dammin. G.1.: Experimental Acadcmic. 19'17. pp. 1-4H2 whole organ transplantation of the liver and of the spleen. Ann. Surg. 19. Merrill. 1.1' .. Murrav. 1.E .. Harrison. 1.H .. Friedman. E.A .. Dealv. 152:374. 1960 J.B .. Jr .. D'lmmin. G.1.: Successful homotransplantation of the kid­ -lJ. StarzL T.E .. Kaupp. H.A. 11' .. Brock. D.R .. Lazarus. R.E .. 10hnson. nt!y hetween non-idcntical twins. N. Engl. 1 Med. 2()2:1251. 196t1 R.V.: Reconstructive prohlems in canine liver homotransplantation 20. Starzl. T.E .. Groth. C.G .. Brettschneider. L.. l'enn. I.. Fulginiti. V.A. with special reference to the postoperative role of hepatic venous Moon. 1.B .. Blandwrd. H .. Martill_ A.J .. 11' .. Porter. K.A.:~Orthotopic 110w. Surg. Gynecol. Obstet. 111:7J:I. 1960 homotransplantation of tht! human liver. Ann. Surg. /()8:J92. 19(,X -l4. Starzl. TE .. Kaupp. H.i\.. lr.: Mass homotransplantation of abdom­ 21. B'lrIlard. eN.: What we have learned ahout h~art transplants. inal ml!ans in dogs. Surg. Forum II :2H. 1%0 1. Thorac. Cardiovasc. Surg. 56:457. I96H -l5. Lnwer: R.R .. Shu-mway. ~N.E.: Studies on orthotopiC homotransplan­ " Dong. L.. as told bv Shu~wav. N.E .. Lower. R.R.: In: Historv of tation of the canine heart. Surg. Forum 1/:1'11. 1%0 Tran~.,plantation: TI;irty-Five Recollections. T erasaki. P. I.. editor. 46. Lower. R.R .. Stofer. R.C .. Slu;mway. N.E.: 1I0movitai transplanta­ Los Angeles. l'ClA Tissue Typing Laboratory. 1991. pp. 4J5-449 tion of the heart. J. Thorac. Cardiovasc. Surg. -11:1%. 1961 2:1. D.:rom. F.. Barbin. F .. Ringoir. S .. Versieck. 1.. Rolly. G .. Bcrzsenv. 47. lower. R.R .. Stofer. R.C .. Hurlev. E.1 .. Shumway. N.E.: Complete Ci .. Vnnu:in:. P.. Vrints. L.: Ten-month survival after lunl! homo­ homograft replacement of the heart and both lungs. Surgl.:ry 50:S42. transplantation in man. 1. Thorac. Cardiovasc. Surg. ()/:HJ5'. 1971 1961 24. Lillehei. R.C.. Simmons. R.L.. Najarian. J.S .. Weil. R .. Uchida. II.. -lX. Jaboulay. M.: Cirdk du reins au pli du coude par soudures arterielles Ruiz. J.O .. Kjell,trand. CM .. Goetz. F.C.: Pancreaticoduodenal al­ ct vClIleuses [Kidney grafts in the antecubital fossa bv artt!rial and lotransplantation: experimental and dinical observations. Ann. Surg. venous anastomosis I. lyon Med. IIJ7:575. I <)Oh I 72A05. I 'no 49. Unger. L: Nierentransplantation IKidnev transplantationJ. Wien 25. (joulet. 0 .. Revillon. Y .. Brousse. N .. lall. D .. Canion. D .. Rambaus. Klin. Wochenschr. -17:57.1. 1910 C .. C.:rf-Bcn,u""an. N .. Buissoll. C .. Ilubert. 1' .. DePotter. S .. 50. Groth. CG.: Landmarks in dinical renal transplantation. Surg. (jl­ :\1uugenot. J.F .. Fischer. ..\ .. Ricour. ('.: Successlul ,mall howe I new I. Obstel. 13-1::1'2..'1. 1972 transplantati"ll ill all infant. Transplantation 53:<)-l0. 19<)2 51. Reel11s1sma. K .. McCracken. B.H .. S<:hlcgel. J.U .. Pearl. M.!\.. 2h. Starzl. T.E.. Row.:. M .. T,.do. S .. Jall'c. R .. Tzaki,. A. \lolIman. A. Pl.:arc.:e. C.W .. DeWitt. CW .. Smith. P.L. I kwitt. R.L.. Flnner. R.L.. b4ulvel. C .. Purter. K.. Vcnkataramanan. R .. Makowka. L.. Du­ Creech. 0 .. Jr.: Renal heterotransplantation In 111an. Ann. Surg. quesnov. R.: Transplantation of mUltiple ahdominal viscera. 160::lX4. I '!hot J.A.M.!\. 2i>1:I-l-l'). 1')1'19 )~. StarLI. T.E .. ~tan:hillro. T.I. .. [\:tt:fS. (J.N .. Kirkpatrick. C.H .. \Vil­ 27. ~'lath.:. ti .. "nllc!. J.L .. Schwarzcnht!rg. L .. Cattan. A .. S" .. hnci(k~r. son_ WEC .. Porter. K.A .. Rillind. D .. Ogden. D.A .. Hitchwck. \1.: 11.I<:matop,lIetic chimer,1 in man .;II<.:r allogenic (homologous I CR .. Waddell. W.R.: R~nal heterotransplantation from baboon to hun<.:-marn\\\ transplantation. B.M.J. 2:lhJJ. 1')Il.' - man: CXpalel1Ce with 6 Gl\es. Trallsplalltalloll 2:752. 19h4 21'1. Bach. F.Il.: Bune-marrow transplantation In a patient "ilh the Wis­ ~J. VOl'Onoy. U.: Sobre bloqueo del aparato rCliculoendotel1al del hom­ kolt-Altlridl "ntlromc. LalKet 2: 1364. 1%8 bre en all!llnaS lormas de illtoxica,ioll pm el sllblimado \' sobre la 29. (ialli. R...\ .. \\cuwlssen. H.J .. Allen. ltD .. Ilung. R .. Good. R.A: transplant

intoxication and the transplantation of the cadaver kidney as a 80. Mannick. J.A. Lochte, H.L.. Ashley. CA. Thomas. E.D .. Ferrebee. method of treatment for the anuria resulting from the intoxication J. I.W.: A functioning kidney homotransplant in the dog. Surgery Siglo Med. 97:296. 1937 46:82l. 1959 54. Starzl. T.E.: Patterns of permissible donor-recipient tissue transfer in 81. Storb. R .. Epstein. R.B .. Bryant. 1.. Ragde, H .. Thomas. E.D.: Mar· relation to ABO blood groups. In: Experience in Renal Transplan­ row grafts by combined marrow and leukocyte infusions in unrelated tation. Philadelphia. Saunders. 1964. pp. 37-47 dogs selected by histocompatibility typing. Transplantation 6:587. 55. Ramsey. G .. Nusbacher. l., Starzl, T.E., Lindsay, G.D.: Isohemag­ 1968 glutinins of graft origin after ABO-unmatched liver transplantation. 82. Epstein. R.B .. Storb. R .. Ragde. H .. Thomas, E.D.: Cytotoxic typing N. Eng!. J. Med. 311:1167. 1984 antisera for marrow grafting in litter mate dogs. Transplantation 56. Hamilton. D.N.H .. Reid. W.A: Yu Yu Voronoy and the first human 6:45, 1968 kidney allograft. Surg. Gynecol. Obstet. 159:289. 1984 83. Hume. D.M .. Jackson. B.T.. Zukoski. CL Lee. H.M .. Kauffman. 57. Kuss. R .. Teinturier. 1.. Milliez. P.: Quelques essais de greffe rein H.M .. Egdahl. R.H.: The homotransplantation of kidneys and of chez l'homme. Mem. Acad. Chir. 77:755, 1951 fetal liver and spleen after total body irradiation. Ann. Surg. 152:354. 58. Dubost. C .. Oeconomos. N .• Nenna, A, Milliez. P.: Resultats d'une 1960 tentative de greffe renale. Bull. Soc. Med. Hop. Paris 67:1372, 1951 84. Rapaport, F.T.. Bachvaroff, R.J.. Mollen. N., Hirasawa. H .. Asano. 59. Serve lie. M .. Soulie, P .. Rougeulle, J.: Greffe d'une rein de supplicie T., Ferrebee. J.W.: Induction of unresponsiveness to major trans­ a une malade avec rein unique congenital, atteinte de nephrite plantable organs in adult mammals. Ann. Surg. 190:461. 1979 chronique hypertensive azatemique. Bull. Soc. Med. Hop. Paris 67: 85. Van Bekkum, D.W.: Bone marrow transplantation: a story of stem 99. 1951 cells. In: History of Transplantation: Thirty-Five Recollections, Ter­ 60. Michon. L.. Hamburger, I .. Oeconomos, N., Delinotte, P., Richet. asaki, P.I.. editor. Los Angeles. UCLA Tissue Typing Laboratory, G .. Vaysse. 1.. Antoine. B.: Une tentative de transplantation renale 1991, pp. 395-434 chez I'homme: aspects medicaux et biologiques. Presse Med. 61: 86. Murray. J.E.. Merrill. J.P., Dammin. GJ .. Dealy, J.B .. Jr.. Walter. 1419.1953 CW., Brooke. M.S .• Wilson. R.E.: Study of transplantation immunity 61. Merrill. I.P .. Murray. J.E .. Harrison, J.H., Guild. W.R.: Successful after total body irradiation: clinical and experimental investigation. homotransplantation of the human kidney between identical twins. Surgery 48:272. 1960 l.A.M.A. 160:277, 1956 87. Murray. J.E .. Merrill. J.P .• Dammin. GJ .. Dealy, J.B .. Jr.. Alexandre. 62. Hume. D.M .. Merrill. I.P .. Miller, B.F., Thorn, G.W.: Experiences G.W .• Harrison. J.H.: Kidney transplantation in modified reCipients. with renal homotransplantation in the human: report of nine cases. Ann. Surg. 156:337. 1962 I. Clin. Invest. 34:327, 1955 88. Hamburger, I .. Vaysse, J .. Crosnier. J., Tubiana, M., Lalanne. CM .• 63. Moore. F.D.: Give and Take. The Development of Tissue Transplan­ Antoine. B .. Auvert, I., Soulier. I.P .• Dormont, 1.. Salmon. C. Mai­ tation. Philadelphia, Saunders, 1964, pp. 1-182 sonnet, M., Amiel. I.L.: Transplantation of a kidney between non­ 64. Billingham, R.E.. Krohn. P.L., Medawar, P.B.: Effect of cortisone on monozygotic twins after irradiation of the receiver: good function at survival of skin homografts in rabbits. B.M.I. 1:1157, 1951 the fourth month. Pre sse Med. 67:1771. 1959 65. Morgan. I.A: The influence of cortisone on the survival of ho­ 89. Hamburger, 1.. Vaysse, I .. Crosnier. 1.. Auvert. J., Lalanne. CL.. mografts of skin in the rabbit. Surgery 30:506. 1951 Hopper. 1.. Ir .. : Renal homotransplantation in man after radiation of 66. Cannon. J.A .. Longmire. W.P.: Studies of successful skin homografts the recipient. Am. I. Med. 32:'1'.54. 1962 in the chicken. Ann. Surg. 135:60. 1952 90. Kuss. R .. Legrain, M .. Mathe. G .. Nedey. R .. Carney. M.: Homulo­ 67. Krohn. P.L.: Effect of cortisone on second set skin homografts in gous human kidney transplantatiun: experience with six patients. rabbits. Bf. J. Exp. Patho!' 35:539. 1954 Postgrad. Med. I. 38:528. 1962 68. Lawler. RH .. West. l.W .. McNulty, P.H., Clancy. EJ .. Murphy, R.P.: 91. Kuss, R.: Human renal transplantation memories. 1951 to 1981. In: Homotransplantation of the kidney in the human. J.AM.A 144:844. History of Transplantation: Thirty-Five Recullectiuns. Terasaki. P.l.. 1950 editor. Lus Angeles. UCLA Tissue Typing Laboratory. 1991. pp. 69. Murray. G .. Holden. R: Transplantation of kidneys, experimentally 37-59 and in human cases. Am. J. SUfl:(. 87:508. 1954 92. Murrav. J.E.: Nobel Prize lecture: the first successful organ trans­ 70. Murrav. J.E.. Merrill. J.P .. Harrison. J.H.: Renal homotransplanta­ plants -in man. In: History of Transplantation: ThirtY·Five" Recollec· tion in id.:ntical twins. Surg. Furum 6:432. 1955 tions. Tcrasaki. P.l.. editor. Los Angeles. UCLA Tissue Typing Lab­ 71. Brown. J .B.: Homugrafting-uf skin: with repurt of success in identical uratory. 1991. pp. 121-14.1 twins. Surgerv 1:558, 1937 93. Guudwin. W.E .. Kaufmann. J.1 .. Mims. M.M .. Turner. RD .. Glas· 72. Schlessinger: B.S .. Schlessinger. I.H .. editors: The Who's Who uf suck. R .. Goldman. R .. Maxwell. M.M.: Human renal transplanta· Nohel Prize Winners 1901-1990. 2nd ed .. Phoenix, AZ, Orvx Press. tion. L Clinical experience with six cases of renal homutransplanta­ 1991 . tion. J. Urol. 89:13. 1963 7.1. Starzl. T.E .. Bilheimer. D.W .. Bahnson. H.T.. Shaw. B.W.. Ir .. Hard­ 94. Schwartz. R .. Dameshek. W.: Drug·induced immunological tokr­ esty. R.L.. Griffith. B.P .. Iwatsuki. S .. Zitelli. B.1 .. Gartner. J.C. Jr.. ance. Nature /83:1682. 195'1 Malatack. J.1 .. Urbach. A.H.: Heart-liver transplantatiun in a patient <)5. Schwartz. R .. Dameshek. W.: The dIccts of 6-mercaptopunn.: on with familial hyperchulesterolemia. Lancet 1:1382. 1984 homograft reactions. J. Clin. Invest. 39:952. 196!l 74. Bilheimer. D.W .. Goldstein, J.L.. Grundv. S.C .. Starz!. T.E., Brown. '16. Meek~r. W .. Cundie. R .. Wein.:r. D .. Varcu. R.L.. Good. R.A: M.S.: Liv.:r transplantatiun provides lo~.density-lipuprotein recep­ Prolongation of skin homograft survival in rabbits bv 6·mercaptopu· tors and lowers plasma chulesterol in a child with humuzyguus rine. Proc. Suc. Exp. Biul. Mt:d. 102:459. 1959 familial hvpt:rcholcslerolemis. N. Engl. J. Med. 311:1658. 1984 97. Caine. R.Y.: Tht: rejection of renal i1omografts: inhibition 111 dogs hy 75. Nossal. G.J.V.: Antihudy production by Single cells. Nature 181:1419. 6-mercaptupurine. Lancet 1:417. 1%0 1958 98. Zukoski, CF.. Lt:c. H.M .. Hume. D.M.: Thc prolongation of func· 7(). Dempster. W.1 .. Lennox. B.. Boag. J.W.: Prolungatiun uf survival uf tional survival llf canine rt:nal homografts hv o-mcrcaptopurin.:. skin homotransplants in the rabbit by irradiation of the hust. Br. J. Surg. Furum 11:470. 1%0 Exp. Pathol. 31:67!l. 1950 99. Caine, R.Y.: [nhihition of the rejection of renal homugralts in dogs 77. Cannon. J.A .. Terasaki. P .. Lungmire. W.P.: Studies of factors influ­ by purine analogues. Transplant. Bull. 28:445. 1961" " encing induced tolerance to skin homografts in the chicken. Ann. 100. Caine. RY .. Murrav. J.E.: Inhihition of the rejection ot r~nal ho­ Surg. 1-If>:27H. 1'157 mograth in dogs hy' Burroughs Wdlcome 57-:!22. Surg. Forum 12: 7'1'.. Main. J.M .. Prehn. R.T.: Successful skin homugrafts after the admin· 118. 19()1 istration of hi\!h dosage x radiatiun and homulugous bone marrow. 101. Caine. R.Y .. Alexandre. G.P.J .. Murrav. J.E.: A study of th.: dkcts of J. Natl. Canee"r lnst. /5:1023. 1955 - drugs in prolonging survival of homologous r.:nal transplants in dogs. 7'1. Trenlln. J.J.: Mortality and skin transplantabilitv in x-irradiated mice Ann. N.Y. Acad. Sci. <)<):743. 1962 receiVing Isologous or heterolugous bone marrow. Proc. Suc. Exp. IO:!. Hitchings, G.H .. Elion. G.B.: The chemistrv and biochemlstrv ot BioI. f\\cd. '12:6'1'.8. 1<)56 purine ~nalugs. Ann. N.Y. Acad. Sci. (){):195: 1954 . 778 World J. Surg. Vol. 24, No.7, July 2000

103. Pierce. J.C .. Varco. R.L.: Induction of tolerance to a canine renal 126. Peacock. 1.H.. Terblanche. J.: Orthotopic homotransplantation of homotransplant with 6-mercaptopurine. Lancet 1:781. 1962 the liver in the pig. In: The Liver. Read. A.E.. editor. London, 104. Zukoski. e.F.. Callaway, J.M.: Adult tolerance induced by 6-methyl Butterworth. 1967, p. 333 mercaptopurine to canine renal homografts. Nature 198:706. 1963 127. CaIne. RY .. White. H.J.O .. Yoffa. D.E.. Maginn. R.R, Binns, R.M., 105. Starzl. T.E.: Host-graft adaptation. In: Experience in Renal Trans­ Samuel. J .R .. Molina. V.: Observations of orthotopic liver transplan­ plantation. Philadelphia. Saunders. 1964. pp. 164-170 tation in the pig. B.M.J. 2:478, 1967 \06. Murray. lE.. Sheil. A.G.R. Moseley. R. Knoght. P.R .. McGavic. 128. CaIne. RY .. White. H.J.O .. Yoffa. D.E .• Binns. R.M .. Maginn. R.R .. J.D .. Dammin. G.J.: Analysis of mechanism of immunosuppressive Herbertson, R.M .. Millard. P.R. Molina, V.P .• Davis, D.R.: Pro­ drugs in renal homotransplantation. Ann. Surg. 160:449. 1964 longed survival of liver transplants in the pig. B.M.J. 4:645. 1967 107. Hopewell. 1.. Caine. R.Y .. Beswick. l.: Three clinical cases of renal 129. Starz!. T.E.: Rejection in unmodified animals. In: Experience in transplantation. B.M.J. 1:411. 1964 Hepatic Transplantation. Philadelphia, Saunders. 1969, p. 184 108. Alexandre. G.P.J .. Murrav. J.E.: Further studies of renal homotrans­ 130. Hunt. A.e.: Pathology of liver transplantation in the pig. In: The plantation in dogs treated by combined Imuran therapy. Surg. Forum Liver. Read. A.E .. editor. London. Butterworth. 1967. p. 337 13:64. 1962 131. Porter. KA.: Pathology of the orthotopic homograft and heterograft. 109. Starzl. T.E .. Demetris. A.J.. Murase. N.• Trucco. M .. Thomson. A.W.• In. Experience in Hepatic Transplantation, Starzl. T.E.. editor. Phil­ Rao. A.S.: The lost chord: microchimerism. Immunol. Today 17:577, adelphia. Saunders, 1969, p. 427 1996 132. CaIne. R.Y .. Sells, R.A., Pena. I.R.• Davis. D.R .• Millard. P.R., 110. Hume, D.M .• Magee. J.H., Kauffman. H.M .• Ir .. Rittenbury. M.S .. Herbertson. B.M .. Binns. R.M .• Davies. D.A.L: Induction of immu­ Prout. G.R .. Jr.,: Renal homotransplantation in man in modified nological tolerance by porcine liver allografts. Nature 223:472, 1969 recipients. Ann. Surg. 158:608. 1963 133. Zimmerman. FA. Davies. H.S .• Knoll. P.P., Gocke. 1.M .. Schmidt. Ill. Murrav. I.E .. Merrill. 1.P .. Harrison. I.H., Wilson. R.E .. Dammin. T.: Orthotopic liver allografts in the rat. Transplantation 37:406. 1984 GJ.: Prolonged survival of human-kidney homografts by immuno­ 134. Kamada. N .. Brons. G., Davies. HJJ.S.: Fully allogeneic liver graft­ suppressive drug therapy. N. Engl. 1. Med. 268:1315. 1963 ing in rats induces a state of systemic nonreactivity to donor trans­ 112. Woodruff. M.F.A .. Robson. J.S .. Nolan. B .. Lambie. A.T.. Wilson. plantation antigens. Transplantation 29:429. 1980 T.!.. Clark. J.G.: Homotransplantation of kidney in patients treated 135. Kamada. N .. Davies. H.f.f.S .. Roser. B.: Reversal of transplantation by preoperative local radiation and postoperative administration of immunity by liver grafting. Nature 292:840. 1981 an antimetabolite (lmuran). Lancet 2:675. 1963 136. Corry. R.J .. Winn, H.I., Russell. P.S.: Primary vascularized allografts 113. Starzl. T.E .• Putnam. e.W .. Halgrimson. e.G .• Schroter. G.T .. Mar­ of hearts in mice: the role of H-2D. H-2K. and non-H-2 antigens in tineau. G .• Launois. 8., Corman. lL.. Penn. I.. Booth. A.S .. Jr .. rejection. Transplantation 16:343, 1973 Groth. e.G .• Porter, K.A.: Cyclophosphamide and whole organ 137. Russell. P.S .. Chase. e.M .. Colvin. R.B .. Plate. 1.M.D.: Kidney trans­ transplantation in human beings. Surg. Gynecol. Obstet. 133:981. plants in mice: an analysis of the immune status of mice bearing 1971 long-term H-2 incompatible transplants. J. Exp. Med. 147:1449. 1978 114. Starz!. T.E .. Groth. e.G .. Putnam. e.w.. Corman. J .. Halgrimson. 138. Starzl. T.E.: Host graft adaptation. In: Experience in Renal Trans­ e.G .. Penn. I.. Husberg. B.. Gustafsson. A.. Cascardo. S .• Geis. P .. plantation. Philadelphia. Saunders. 1964. pp. 168-170 [watsuki. S.: Cyclophosphamide for clinical renal and hepatic trans­ 139. Starzl. T.E.: Efforts to mitigate or prevent rejection. In: Experience plantation. Transplant. Proe. 5:511. 1973 in Hepatic Transplantation. Philadelphia. Saunders. 1969. pp. 228- 115. Starzl. T.E.. Marehioro. T.L. Porter. K.A .. Iwasaki. Y .. Cerilli. G.J.: 233 The us.: of hetaologous antilymphoid agents in canine renal and 140. Steinman. R.M .. Cohn. Z.A.: Identification of a novel cell type in liver homotransplantation and in human renal homotransplantation. peripheral lymphoid organs of mice. L Morphology, quantitation. Surg. Gynecol. Obstet. 124:301. 1967 tissue distribution. 1. Exp. Med. 137:1142. 1973 116. Mcdawar. P.B.: Transplantation of tissues and organs: introduction. I·H. Simonsen. M.: On the acquisition of tolerance by adult cells. Ann. Br. Med. Bull. 21:97. 1965 N.Y. Acad. Sci. 87:382. 1960 117. Woodrutt. M.F.A .. Woodruff. H.G.: The transplantation of normal 142. Burnet. F.M.: The Clonal Selection Theory of Acquired Immunity. tissues: with special reference to auto- and homo transplants of thy­ Nashville. 1':'1. Vanderbilt University Press. 1959. p. 59 roid and spleen in the anterior chamber of the eye. and subcutane­ I·a Talmage. D.W.: [mmunological specificitv. Science 129:1649. 1959 ously. in guinea pigs. Philos. Trans. 13. 234:559. 1950 144. Burnet. F.\1.: The new approach to immunology. N. Engl. 1. Med. II~. Woodrutt·. M.F.A.: Evidence of adaptation in homografts of normal 264:24. 1961 tissue. In: Biological Problems of Grafting. Medawar. P.B.. editor. 145. Miller. J.F.A.P.: Immunological function of the thymus. Lancet Oxford. Blackw;11. 1959. pp. 83-94 ~ 2:748. 1961 119. Starzl. T.E.: Precepts of renal homotransplantation applied to ho­ 146. Miller. I.EA.P.: Effect of neonatal thymectomy on the immunolog­ mografting of other organs. In: Experience in Renal Transplantation. ical responsiveness of the mouse. Proc. R. Soc. Lond. [Biol.J 156:415. Philadelphia. Saunders. 1964. pp. 360-362 1962 120. Starzl. T.E .. Kaupp, H.A .. lr .. Brock. D.R. Butz. G.W .. Jr.. Linman. 147. Starz!. T.E .. Marchioro. T.L. Talmage. D.W .. Waddell. W.R.: Sple­ 1.W.: Homotransplantation of multiple visceral organs. Am. J. Surg. nectomv and thymectomy in human renal homotransplantation. 103:219. 1%2 Proc. Soc. Exp. Biol. Med. 113:929. 1903 121. Murase. N.. Demetris. A.J .. Kim. D.G .. Todo. S.. Fung. J.1 .. Starzl. 148. Starzl. T.E.. Porter. KA .. Andres. G .. Groth. CG .. Putnam. e.W .. T.E.: Rejection of the multivisccral allografts in rats:' a se(juential Penn. L Halgrimson. e.G .. Starkie. S.J .. Brettschneider. L: Thymec­ analvsis with wmparison to isolated orthotopic small bowel and liver tomy and re-nal homotransplantation. Din. Exp. Immunol. 6:H03. grafts. Surgery 11I8:1i80. 1990 1970 122. Murasc. N .. Dcmetris. A.1.. Matsuzaki. T .. Yagihasi. A .. Tlldo. S.. ]-\9. McGregor. D.D .. Guwans. J.L.: Antibody response of rats d.:pleted Fung. L Starzl. T.E.: Long survival in rats after'multivisceral versus of lymphocytes by chronic drainage from th.: thoracic duct. J. Exp. isol;ted small howel allotr~nsplantation under FK 506. Surgery 1 f(): Med. 117:."\03. 1%3 S7. 1991 150. McGregor. D.D .. Gowans. J.L.: Survival of homol!rafts of skin in rats 123. Starzl. T.E .. Marchioro. T.L.. Porter. K.A.. Tavlor. P.D .. Faris. T.D .. depleted of I"mphocytes by chronic drainag.: from the thoracic duct. H<:rrmann. T.1 .. Hlad. C.J .. Waddell. W. R.:· Factors determinin1! Lancet 1:629. 1964 short- and long-term survival aftef orthotopIC liver homotransplan~­ 151. Algire. G.H .. Weaver. 1.M .. Prehn. R.T.: Studies on tissue homo­ tation in the do!!. Surgery 58: 131. 1965 tra'nsplantation IU mice using diffusion chamher methods. Ann. N.Y. 12·t Starzl. T.E.: Elforts to mitigate or prevent rcj.:ction. In: Experienc.: Acad. Sci. 1l-l:IOO9. 1957 in Hepatic Transplantation. Philadelphia. Saunders. ] 969. pp. 20-'- 152. Starzl. T.E .. Kaupp. H.A .. Jr .. Brock. D.R .. Linman. J.W.: Studies on 206 the rejection of the transplanted homoll'!!ous dog liver. Surg. Gy­ 125. (\lrdicr. G .. Garnier. H .. Cllll. J.P .. Camplez. 1' .. Gorin. 1.1' .. Clol. necol. Obstet. J 12: 135. 190 I P.H.. Rasslnler. l.P .. Nizza. M.. Levy. R.: La 1!fetfe de foie ortho­ 153. Elkinlon. J.R.: Moral prohlems III the l"

154. Starzl. T.E .. Marchioro. T.L.. Rifkind. D .. Holmes. J.H .. Rowlands. tion, purification and immunosuppressive properties in man. Ann. D.T., Jr.. Waddell. W.R.: Factors in successful renal transplantation. Surg. 170:617. 1969 Surgery 56:296. 1964 177. Kohler. G., Milstein. C: Continuous culture of fused cells secreting 155. Rifkind. D.: Infectious diseases associated with renal transplantation. antibody of predefined specificity. Nature 256:495, 1975 In: Experience in Renal Transplantation. Starz!. T.E .. editor. Phila­ 178. Cosimi. AB .. Colvin, R.B .• Burton. R.C, Rubin. R.H .. Goldstein. G .. delphia, Saunders. 1964. pp. 213-238 Kung, P.C .. Hansen. W.P., Delmonico. F.L., Russell. P.S.: Use of 156. Starzl. T.E.: Discussion of Murray. J.E .. Wilson. R.E .. Tilnev. N.L.. monoclonal antibodies to T-cell subsets for immunological monitor­ Merrill, J.P., Cooper, W.C. Birtch. AG .. Carpenter. CB .. · Hager. ing and treatment in recipients of renal allografts. N. Eng\. J. Med. E.B., Dammin. G.J .. Harrison, H.: Five years experience in renal 305:308. 1981 transplantation with immunosuppressive drugs. Ann. Surg. 168:416. 179. Dreyfuss. M., Harri, E.. Hofmann. H., Kobel, H., Pache. W .. 1968 Tscherter. H.: Cyclosporin A and C; new metabolites from Tricho­ 157. Penn, I., Hammond. W., Brettschneider. L.. Starz!. T.E.: Malignant derma polysporum (Link ex Pers) Rifai. Eur. I. App\. Microbiol. lymphomas in transplantation patients. Transplant. Proc. 1: 106, 1969 3:125, 1976 158. Starzl, T.E., Penn, I., Putnam, CW.. Groth. CG .. Halgrimson. CG.: 180. Ruegger, A. Kuhn, M., Lichti, H., Loosli, H.R., Huguenin. R., Iatrogenic alterations of immunologic surveillance in man and their Quinquerez, C., von Wartburg, A: Cyclosporin A, ein immunosup­ influence on malignancy. Transplant. Rev. 7: 112. 1971 pressiv wirksamer Peptidmetabolit aus Trichoderma polysporum 159. Hill. R.B., Jr., Rowlands, D.T., Rifkind. D.: Infectious pulmonary (Link ex Pers) Rifai. Helv. Chim. Acta 59:1075, 1976 disease in patients receiving immunosuppressive therapy for organ 181. Petcher, T.I., Weber, H.P., Ruegger, A: Crystal and molecular transplantation. N. Eng!. J. Med. 271:1021, 1964 structure of an iodo-derivative of the cyclic undercepeptide cyclo­ 160. Rifkind. D .• Starz!. T.E .. Marchioro, T.L., Waddell. W.R .. Rowlands. sporin A Helv. Chim. Acta 59:1480, 1976 D.T .. Jr., Hill. R.B.. Jr.: Transplantation pneumonia. J.A.M.A. 189: 182. Borel, J.F.: Comparative study of in vitro and in vivo drug effects on 808. 1964 cell-mediated cytotoxicity. Immunology 31:631. 1976 161. Van Thiel, D .. Igba!. M .. Jain. A, Fung. 1.. Todo. S .. Starz!. T.E.: 183. Borel, I.F.• Feurer, C. Gubler, H.U .. Stahelin. H.: Biological effects Gastrointestinal and metabolic problems associated with immuno­ of cyclosporin A; a new antilymphocytic agent. Agents Actions 6:468. suppression with either cyclosporine or FK 506 in liver transplanta­ 1976 tion. Transplant. Proc. 22:37. 1990 184. Borel. I.F .• Feurer, C, Magnee. C. Stahelin, H.: Effects of the new 162. Iwasaki, Y .• Porter, K.A., Amend, I.R., Marchioro. T.L., Zuhlke, V., anti-lymphocytic peptide cyclosporin A in animals. Immunology 32: Starzl. T.E.: The preparation and testing of horse antidog and anti­ 1017, 1977 human anti lymphoid plasma or serum and its protein fractions. Surg. 185. Kostakis. AJ., White, D.J.G., CaIne. R.Y.: Prolongation of rat heart Gyneco!. Obstet. 124: 1, 1967 allograft survival by cyclosporin A Int. Res. Commun. Syst. Med. Sci. 163. Woodruff. M.F.A .. Anderson. N.F.: Effect of lymphocyte depletion 5:280. 1977 by thoracic duct fistula and administration of anti-lymphocytic serum 186. Caine, R.Y.. White. DJ.G.: Cyclosporin A; a powerful immunosup­ on the survival of skin homografts in rats. Nature 200:702, 1963 pressant in dogs with renal allografts. Int. Res. Commun. Syst. Med. 164. Franksson. C. Blomstrand, R.: Drainage of the thoracic lymph duct Sci. 5:595. 1977 during homologous kidney transplantation in man. Scand. I. Urol. 187. Caine. R.Y., White, DJ.G., Rolles. K., Smith. D.P., Herbertson. Nephrol. 1:123, 1967 B.M.: Prolonged survival of pig orthotopic heart grafts treated with 165. Starzl. T.E., Weil. R .. III. Koep. L.J.. Iwaki. Y.. Terasaki. P.I.. cyclosporin A Lancet 1:1183. 1978 Schroter. G.PJ.: Thoracic duct drainage before and after cadaveric 188. Caine. R.Y .• White. DJ.G .• Pentlow. B.D .• Rolles. K.. Syrakos. T.. kidney transplantation. Surg. Gyneco\. Obstet. U9:815. 1979 Ohtawa. T .. Smith. D.P .. McMaster. P .. Evans. D.B .• Herbertson. 166. Starzl. T.E .• Klintmalm. G.B.G .. Iwatsuki. S.. Schroter. G., Wei!. R.. B.M., Thiru. S.: Cyclosporin A; preliminary observations in dogs with III: Late follow-up after thoracic duct drainage in cadaveric renal pancreatic duodenal allografts and patients with cadaveric renal transplantation. Surg. Gyneco!. Obstet. 153:377. 1981 transplants. Transplant. Proc. II :860. 1979 167. Slavin. S .. Reitz. B.• Bieber. c.P.. Kaplan. H.S .. Strober. S.: Trans­ 189. Green. CJ.. Allison. A.C: Extensive prolongation of rabbit kidney plantation tolerance in adult rats using total Ivmphoid irradiation allograft survival after short-term cyclosporin A treatment. Lancet (TLI): permanent survival of skin. heart. and marrow allografts. J. 1:1182.1978 Exp. Med. J.J7:700. 1978 190. Caine. R.Y .. White. DJ.G .. Thiru. S .. Evans. D.B .. McMaster. P .. 168. Najarian. J.S .. Ferguson. R.M .. Sutherland. D.E.R .. Slavin. S .. Kim. Dunn. D.C .. Craddock. G.N .• Pentlow. B.D .. Rolles. K.: Cyclosporin T .. Kersey, T .. Simmons. R.L.: Fractionated total lymphoid irradia­ A in patients receiving renal allografts from cadaver donors. Lancet tion as preparative immunosuppression in high-risk renal transplan­ 2: 1323. 1978 tation. Ann. Surg. 196:442. 1982 191. Caine. R.Y .• Rolles. K .• White. DJ.G .. Thiru. S .. Evans. D.B .. Mc­ 169. Myburgh. AJ.. Smit. AJ .• Meyers. M.A .. Botha. J.R .. Browde. S .. Master. P .. Dunn. D.C. Craddock. G.N .. Henderson. R.G .. Aziz. S.. Thomson. P.D.: Total lymphoid irradiation in renal transplantation. Lewis. P.: Cyclosporin A initially as the only immunosuppressant in World J. Surg. 10:369. 1986 34 recipients of cadaveric organs; 32 kidneys. 2 pancreases. and 2 170. Metchnikoff. I.: Etude sur la resorption des cellules. Ann. Inst. livers. Lancet 2: t033. 1979 Pasteur 13:737. 1899 192. Starzl. T.E .. Wei!. R .. III. Iwatsuki. S.. Klintmalm. G .. Schroter. 171. Inderbitzen. T.: Histamine in allergic responses of the skin. In: Henry G.P.J .• Koep. L.J.. Iwaki. Y.. Terasaki. P.I.. Porter. K.A: The use of Ford Hospital International Symposium on Mechanisms of Hyper­ cyclosporin A and prednisone in cadaver kidney transplantation. sensitivity. Shafer. 1.H .. LeGrippo. G.A. Chase. M.W .. editors. Bos­ Surg. Gynecol. Obstet. 151: 17. 1980 ton. Little. Brown. 1959. pp. 493-491) 193. Starz\. T.E .. Klintmalm. G.B.G .. Porter. K.A .. Iwatsuki. S.. Schroter. 172. Waksman. B.Y .. Arbouys. S .. Arnason. B.G.: The use of specific G.P.J.: Liver transplantation with use of cyclosporin A and pred­ "Iymphocvte" antisera to inhibit hypersensitive reactions of the "de­ nisone. N. Eng!. J. Med. 305:266. 1981 layed" tvpe. J. Exp. Med. I J.i:91)7. 1%1 194. Reitz. B.A. Wallwork. J.L.. Hunt. S.A .. Pennock. J.L. Billingham. 173. Levev. R.H .. Medawar. P.B.: Nature and mode of action of antilvm­ R.E .• Over. P.E .. Stinson. E.B .. Shumwav. N.E.: Heart-lung trans­ phocYtic antiserum. Proc. Nat\. Acad. Sci. U.S.A 56: 1130. 1966' plantation: successful therapy for patient~ With pulmonary vascular 174. Monaco. AP .. Wood. M.L.. Russell. P.S.: Adult thymectomy: effect disease. N. Eng\. J. Med. 306:557. 19t12 on recovery from immunologic depression in mice. Science I·N:43~. 195. Griffith. B.P .• Hardestv. R.L.. Deeb. G.M .. Starz!. T.E.. Bahnson. 1905 H.T.: Cardiac transplantation with cyclosporin A and prednisone. 175. Monaco. AP .. Wood. M.L.. Russell. P.S.: Studies of heterologous Ann. Surg. 196:324. 1982 antllymphocvte serum in mice. III. Immunologic tolerance and-chi­ 1%. Cooper. J.: The evolution of techniques and indications for lung merISm produced across the H-2 locus with adult thvmectomy and transplantation. Ann. Surg. 212:249. 1(1)0 antilymphocvte serum. Ann. N.Y. Acad. Sci. 129:190. 1%6 197. Starzl. T.E.. Todo. S .. Fung. J.. Dt:metns. AJ .. Venkataramanan. R .. 176. Najarian. 1.S .. Simmons. R.L.. Gewurz. H .. Moberg. A. Merkel. F .. Jain. A: FK 506 for hum~n liver. kidney and pancreas transplanta­ ~loore. G.A.: Anti-serum to cultured human ivmphoblasts: prepara- tion. Lancet 2: 1000. 1(81) 780 World J. Surg. Vol. 24. No.7, July 2000

198. Kino. T. Hatanaka. H .. Miyata. S. .lnamura. N .. Nishiyama. M .. 217. Starz!' T.E.. Brittain. R.S .. Stonington. O.G .. Coppinger. R.W .. Wad­ Yajima. T.. Goto. T.. Okuhara. M .. Kohsaka. M.. Aoki. H .. Ochiai. dell. W.R.: Renal transplantation in identical twins. Arch. Surg. T.: FK500. a novel immunousppressant isolated from Streptomyces. 86:000. 1%3 II. Immunosuppressive effect of FK-500 in vitro. J. Antibiot (Tokyo) 218. Owens. TC.. Prevedel. A.E .. Swan. H.: Prolonged experimental -10:1250. Ill87 occlusion of thoracic aorta during hypothermia. Arch. Surg. 70:95. IlJ9. Ochiai. T.. Nakajima. K.. Nagata. M .. Suzuki. T.. Asano. T.. Uc­ 1955 matsu. T. Goto. T .. Hori. S.. Kinmochi. T .. Nakagouri. T .. Isono. K.: 219. Starzl. TE.: Experience in Renal Transplantation. Philadelphia. Effect of a new immunosuppressive agent. FK500. on heterotopic Saunders. 1%4. pp. 68-71 allotransplantation in the rat. Transplant. Proc. 19: 1284. 1987 220. Marchioro. T.L.. Huntlev. R.T .. Waddell. W.R .. Starzl. TE.: Extra­ 200. Murase. N.. Todo. S.. Lee. P-H .. Lai. H.S .. Chapman. F.. Nalesnik. corporeal perfusion fur ;,htaining postmortem homografts. Surgery M.A .. Makowka. L.. Starz!. TE.: Heterotopic heart transplantation 5-1:900. 1%3 in the rat under FK-500 alone or with cyclosporine. Transplant. Proc. 221. Ackerman. J.R .. Snell. M.E.: Cadaveric renal transplantation. Br. J. 19:71. 1987 Uro!. .,t():SI5. 1908 201. Lee. P .. Murase. N.. Todo. S.. Makowka. L.. Starz!. T: The immu­ 222. Merkel. F.K .. Jonasson. 0 .. Bergan. J.1.: Procurement of cadaver nosuppressive effects of FR 900500 in rats receiving heterotopic donor organs: evisceration techniques. Transplant. Proc. 4:58S. 1972 cardiac allografts. Surg. Res. Commun. 1:325. 1987 223. Starz!. TE.. Hakala. TR.• Shaw. B.W .. Jr .. Hardesty. R.L. 202. Todo. S.. Podesta. L.. ChapChap. P.. Kahn. 0 .. Pan. C-E .. Ueda. Y .. Rosenthal. T.E .. Griffith. B.P .. Iwatsuki. S .. Bahnson. H.T.: A flexible Okuda. K.. Imventarza. 0 .. Casavilla. A. Demetris. A1.. Makowka. procedure for mUltiple cadaveric organ procurement. Surg. Gynecol. L.. Starz!. T.E.: Orthotopic liver transplantation in dogs receiving Obstet. 158:223. 191'4 FK-506. Transplant. Proc. 19:64. 1987 224. Starz!. TE.. Miller. C. Broznick. B.. Makowka. L.: An improved 203. Todo. S .. Ueda. Y.. Demetris. J.A. Imventarza. 0 .. Nalesnik. M .. technique for multiple organ harvesting. Surg. Gynecol. Obstet. 165: Venkataramanan. R.. Makowka. L.. Starzl. TE.: Immunosuppres­ 343. 1987 sion of canine. monkey. and baboon allografts by FK 500 with special 22S. Carrel. A .. Lindbergh. C.A.: The Culture of Organs. New York. reference to svnergism with other drugs. and to tolerance induction. Hoeber. 1931' Surgery IIN:i19. 1'988 - 226. Ackerman. J.R .. Barnard. CN.: A report on the successful storage of 204. Todo. S.. Demetris. A. Ueda. Y .. Imventarza: 0 .. Cadolf. E .. Zeevi. kidneys. Br. J. Surg. 53:525. 1%6 A .. Starz!' T.E.: Renal transplantation in baboons under FK SOo. 227. Brettschneider. L.. Daloze. P.M .. Huguet. C. Porter. K.A. Groth. Surgery 106:444. 1989 D.G .. Kashiwagi. N .. Hutchison. D.E .. Starz!. T.E.: The use of com­ 20S. Fung. J.J .. Todo. S.. Jain. A .. McCauley. 1.. Alessiani. M.. Scotti. C. bined preservation techniques for extended storage of orthotopic Starz!. TE.: Conversion of liver allograft recipients with cyclosporine liver homografts. Surg. Gynecol. Ohstet. 126:203. 1%8 related complications from cyclosporine to FK S06. Transplant. Proc. 228. Belzer. F.O .. Ashby. B.S .. Dunphy. J.E.: 24-Hour and 72 hour pres­ 22:6. 1990 ervation of canine kidneys. Lancet 2:530. 1967 200. Armitage. J.M .. Kormos. R.L.. Griffith. B.P .. Hardestv. R.L.. Fricker. 229. Collins. G.M .. Bravo-Shugarman. M.. Terasaki. P.I.: Kidney preser­ F.1 .. Stuart. R.S .. Marrone. G.C. Todo. S.. Fung. J .. Starz!. TE.: The vation for transportation: initial perfusion and 30 hours ice storage. clinical trial of FK SOo as primary and rescue immunosuppression in Lancet 2:1219. 1909 cardiac transplantation. Transplant. Proc. 23: 1149. 1991 230. Schalm. S.W.: A simple and clinicallv applicable method for the 207. Todo. S.. Fung. J.1 .. Starzl. T.E .. Tzakis. A. Demetris. A1.. Kormos. preservation of a liver homograft. Thesis. University of Leyden. R .. Jain. A. Alessiani. M .. Takava. S.: Liver. kidnev. and thoracic Holland. IlJ6X organ transplantation under FK 500. Ann. Surg. 212~295. 1990 231. Benichou.1.. Halgrimson. CG.. Weil. R .. Ill. Koep. L.J.. Starzl. T.E.: 208. Starzl. TE.. Fung. J.. Jordan. M .. Shapiro. R.. Tzakis. A. McCaulev. Canine and human liver preservation for () -18 hours by cold infu­ J .. Johnston. 1.. Iwaki. Y.. Jain. A. Alessiani. M .. Todo. S.: Kidnev sion. Transplantation 2-1:407. 1977 transplantation under FK 500. J.AM.A 26-1:03. Ill90 . 232. Wall. W.1 .. Caine. R.Y .. I-Ierbertson. B.M .. Baker. P.G .. Smith. 0.1' .. 209. Starzl. T.E .. Donner. A. Eliasziw. M.. Stitt. L.. Meier. P.. Fum!. J.1 .. Underwood. 1.. Kostakis. A. Williams. R.: Simple hvpothermic pres­ McMil'hael. J.P .. Todo. S.: Randomized trialomania"! The "lnulti­ ervation for transporting human livers long uistanc<:s for transplan­ center liver transplant trials. Lancet 3-1fi: I 34i,. 1995 tation. Transplantation 23:210. 1977 210. Fun~. J.J .. Tm.lll. S.. Tzakis. A. Demetrrs. A .. Jain. A.. Ahu-Elma~d. 2.1.1 Jamieson. N.V .. Sundberg. R .. Limkll. S.. LdraVllSO. R .. Kalavoglu. K.. Ale,siani. M .. Starzl. T.E.: Conversion of liver allograft recipients M .. Southard. J.l1.. Bclz<:r. F.O.: Successful 24- to JO-hour pres<:r­ from cydosporine to FK506-based immunosuppression: henelits and vat ion of the canine liwr: a preliminary rermt. Transplant. Proc. pitfalls. Transplant. Proc. 23: 14. 199 I 29(Suppl. 1):1)45. IlJX8 211. Fung. J.J .. Todo. S .. Jain. A. Demetris. A.J .. McMichael. J.P .. Starz!. 2.14. Kalayoglu. M.. Sollinger. W.H .. Stralta. IU .. D·Alessandro. AM .. T.E.: The Pittsbur~h randomized trial of tacrolimus versus l.-yclospor­ HolIman. R.M .. Pirsch. J.D .. Belzer. F.O.: Extended preservation of ine for liver transplantation. J. Am. Coil. Surg. 183: /17. 19% the liver for clinical transplantation. Lancet 1:()17. 1988 212. Neuhaus. 1' .. Pichlmavr. R.. Williams. R .. European FK SOil Multi­ ~35, Toun. S .. N~ry. J .. Yi.lna~a. K.. Podesta. L.. Gordon. R.D .. Starzl. centre Lin:r Studv Group: Randomised trial comparin~ tacrolimus T.E.: Extended preservation of human liver grafts with UW solution. (FK 50il) and cvclllsporin in prevention of liver allograft rejection. J.AM.A 261:711. I'IXI) Lancet 3-1-1:423. 1')1)4 236. HolIman. IL Sollinger. II.. Kalavol!lu. M .. Iklzer. F.O.: Use of UW 2 Ll. Klintlllallll. G .. U.S. Multicenter FK 506 Liv.:r StuJy (iIllUP: i\ solution lor kidnev'transplantati'lll{. Transplantation -Ild38. II)XX L'llmpanSOIl ot tacrolimus (FK SOil) and cvdllpsurine for immuno­ 237. Wahlberg. J.A .. Love. R .. Lanuegaard. L.. Southard. J.II.. Belzer. ,uppression In liver transplantation. N. Eng!. J. Med. 33/:1110. 1994 F.O.: 72-HoUl" preservation of the cantne panlTeas. Transplantation 214. St'lrzl. T.E.. Abu-Ellllal!d. K.. TLakis. A.. Fung. 1.1.. Porter. K.A .. -I3:S. 19X7 fodo. S.: Selected topics on FK SOil: With special rderences [(l 2JX. Ploeg. R.J.. Goossens.D .. McAnultv. J.F,. Smuhard. J.H .. Iklzer. rescue of extrahepatic whole organ gratts. tr,lI1splantation of "fm­ F.O.: Successful 72-h'1lIr cold storage of dog kidnevs with UW solu­ hidden organs". side dIccts. mechanisms. and practical pharmacoki­ tion. Transplantation -II): IlJ I. I')X8 netics. Transplant. !'roc. 23:914. I'NI 239. Ueda. Y.. Todo. S.. Imventarza. 0 .. Furukawa. 1-1 .. Oks. A.. Wu. 215. Todo. S.. Tzaki,. A.G .. Abu-Ellllagd. K.. Reyes. 1.. Nakamura. K.. Y.M .. Ok!uma. S.. Starzl. T.E.: The U\V solution tor canine kidnev Casavilla. A. Selhy. R.. Nour. I3.M.: Wright. If .. Fung. J.1.. Demetris . preservation: its specilic ellcct Oil renal hemodvnamlcs and micr,i­ .. \.1.. \';,n Thiel. ·D.H .. Starzl. TE.: l~ltcstll1al tr:,nsplantation in vdsculature. Trdnsplantation ./8:l)l.l IlIX!) composile \'is,eral gratts or alone. Ann. Surg. 2J6:223. 19'12 240. Belzer. 1'.0 .. S"utilard. J.II.: Principles "t ,,,lid-organ preservati"n 216. Todll. S.. T lakis. AG .. Abu-Elmal!d. K.. Reves. J.. Funl!. J.J .. by cold storage. Transplantation -I5:h7."'. I'lXX Casavilla. A .. Nakamura. K.. Yagih~shi. A .. Jilin. A. Mura~se. N .. 241. Todo. S.. Podesta. L.. Ueda. Y.. Imvcntarza. 0 .. Casavilla. A.. Oks. Iwaki. Y.. DCl11etris. A1.. V,1Il Thiel. D .. Starzl. TE.: CadaveriC sl11all A.. Okuda. K.. Nalesnik. ~\.. Vcnkataramanan. R .. Starzl. T.E.: .-\ howel and small bowel-liver transplantatIOn 111 human;,. Transplan­ comparison ot UW with otha ",Iutions tor lin:r preservation in Lition 53:.'il'l. 19'12 dogs. Clin. fransplant. 3:2:'.'. l'IXlj _._------

Stanl: History of Clinical Transplantation 781

242. Starzl. TE .. Nalesnik. M.A .. Porter. K.A. Ho. M .. !watsuki. S .. L.. Terasaki. P.1.: Shwartzman reaction after human renal transplan­ Griffith. RP .. Rosenthal. JT. Hakala. TR.. Shaw. B.W. Jr.. Hard­ tation. N. Eng!. 1. Med. 278:642. 1968 esty. R.L.. Atchison. R.W .. Jaffe. R .. Bahnson. H.T.: Reversibilitv of 266. Patel. R.. Terasaki. P.I.: Significance of the positive crossmatch test lymphomas and Iymphoproliferative lesions developing under cy~lo­ in kidney transplantation. N. Eng!. J. Med. 280:735. 1969 sporin-steroid therapy. Lancet 1:583. 1984 267. Simpson. K.M .. Bunch. D.L.. Amemiva. H .. Boehmig. HJ .. Wilson. 243. Starzl. TE.: The mother lode of liver transplantation: with particular CB .. Dixon. FJ .. Coburg. A.1.: Humoral antibodies and coagulation reference to our new journal. Liver Transplant. Surg. of: I. 199H mechanisms in the accelerated or hyperacute rejection of renal ~ ..... Starzl. TE.. Marchioro. TL. Rowlands. D.T .. Jr.. Kirkpatrick. CH .. homografts in sensitized canine recipients. Surgery 68:77. 1970 Wilson. WECo Rifkind. D .. Waddell. W.R.: Immunosuppression 26R. Boehmig. H.J.. Giles. G.R .. Amemiya. H .. Wilson. C.B .. Coburg. after experimental and clinical homotransplantation of the liver. AJ .• Genton. E .. Bunch. D.L.. Di.xon. F.1 .. Starzl. T.E.: Hyperacute Ann. Surg. 160:411. 1964 rejection of renal homografts: with particular reference to coagula­ 245. Marchioro. T.L.. Porter. K.A. Dickinson. T.e.. Faris. TD.. Starzl. tion changes. humoral antibodies. and formed blood elements. T.E.: Physiologic requirements for auxiliary liver homotransplanta­ Transplant. Proc. 3: 1105. 1971 tion. Surg. Gyneco!. Obstet. 121:17. 1965 269. Starzl. T.E .. Boehmig. H.1 .. Amemiya. H., Wilson. CB., Dixon. FJ .• 246. Starzl. T.E .. Francavilla. A. Halgrimson. CG .. Francavilla. F.R .. Giles. G.R .. Simpson, K.M .. Halgrimson. CG.: Clotting changes. Porter. K.A. Brown. T.H .. Putnam. CW.: The origin. hormonal including disseminated intravascular coagulation. during rapid renal­ nature. and action of hepatotrophic substances in ~portal venous homograft rejection. N. Eng!. J. ~ed. 283:383, 1970 blood. Surg. Gynecol. Obstet. 137: 179. 1973 270. Myburgh. l.A_ Cohen. I.. Gecelther. L.. Meyers, AM., Abrahams. 247. Starzl. TE.. Porter. K.A. Putnam. CW.: !ntraportal insulin protects C. Furman. K.I.. Goldberg. B .. van Blerk. PJ.: Hyperacute rejection from the liver injury of portacaval shunt in dogs. Lancet 2: 1241. 1975 in human-kidney allografts Shwartzman or Arthus reaction? N. Eng!. 248. Francavilla. A .. Hagiya. M .. Porter. K.A. Polimeno. L.. !hara. I.. 1. Med. 281:131. 1969 Starzl. TE.: Augmenter of liver regeneration (ALR): its place in the 271. Ct:rilli. 1.. Brasile. L.. Galouzis. T. Lempert. N .. Clark. 1.: The universe of hepatic growth factors. Hepatology 20:747. 1994 vascular endothelial cell antigen system. Transplantation 39:286. 249. Starzl. TE.. Jones. A.F .. Terblanche. 1.. Usui. S.. Porter. K.A .. 1985 Mazzoni. G.: Growth-stimulating factor in regenerating canine liver. 272. Brasile. L.. Zerbe. T .• Rabin. B.. Clarke. 1.. Abrahms. A. Cerilli. J.: Lancet 1:127.1979 Identification of the antibody to vascular endothelial cells in patients 250. Hagiya. M.. Francavilla. A.. Polimeno. L.. [hara. I.. Sakai. H .. Seki. undergoing cardiac transplantation. Transplantation 40:672. 1985 T .. Shimonishi. M.. Porter. K.A .. Starzl. T.E.: Cloning and sequence 273. Knechtle. SJ .. Halperin. E.C. Bollinger. R.R.: Xenograft survival in analysis of the rat augmenter of liver regeneration (ALR) gene: two species combinations using total-lymphoid irradiation and cyc\o­ expression of biology active recombinant ALR and demonstration of sporin. Transplantation 43: 173. 1987 tissue distribution. Proc. Natl. Acad. Sci. U.S.A 91:8142. 1994 274. Gubernatis. G .• Lauchart. W .. Jonker. M .• Steinhoff. G .• Bornn­ 251. Giorda. R .. Hagiya. M .. Seki. T.. Shimonishi. M .. Sakai. H .• Michael­ scheuer. A .. Neuhaus. P .. Vanes. A.A.. Kemnitz. 1.• Wonigeit. K.. son. 1.. Francavilla. A.. Starzl. TE.. Trucco. M.: Analysis of the Pichlmayr. R.: Signs of hyperacute rejection of liver grafts of rhesus structure and expression of the ALR gene. Mol. Med. 2:97. 1996 monkeys after donor-specific presensitization. Transplant. Proc. 19: 252. Starzl. TE.. Demetris. Al .• Van Thiel. D.H.: Medical progress: liver 1082. 1987 transplantation. N. Engl. J. Med. 32/:1014. 1989 275. Merion. R.M .. Colletti. L.M.: Demonstration of hyperacute rejection 253. Starzl. T.E.: The little drummer girls In: The Puzzle People. Pitts­ (HAR) in outbred large animal model of liver transplantation burgh. University of Pittsburgh Press. 1992. pp. 318-333 (LTX). Transplantation ·1<1:861. 1990 254. Snell. G.D.: Methods for the study of histocompatibility genes. 276. Takaya. S.. Bronsther. 0 .. Iwaki. Y .. Nakamura. K.. Abu-Elmagd. K.. 1. Gt:net. -+Immunogenetics: histocompatibility antigens-genetics. Fung. J.1 .• Starzl. T.E.: The adverse impact on liver transplantation structure and function. In: A History of Transplantation Immunol­ of using positive cytotoxic crossmatch donors. Transplantation 53: ogy. San Diego. Academic. 1997. pp. 13/-182 400. 1992 256. Dausset. J.: Iso-Ieuco-anticorps. Acta Haematol 20: 156. 1958 277. Starzl. T.E .. Demetris. A.1.. Todo. S .. Kang. Y .. Tzakis. A.. Du­ 257. Van Rood. JJ .. Ennisscs. 1.G .. van Leeuwen. A.: Leucocvte anti­ quesnov. R .. Makowka. L.. Banner. B.. Concepcion. W .. Porter. K.A.: bodies in sera from pregnant women. Nature 18/: 1735. 19~H Evidence for hyperacute rejection 01 human liver grafts: thl! case of 25H. Terasaki. P.L. McClelland. J.D.: Microdroplet assay of human serum the canary kidneys. Clin. Transplant. 3:.17. 19H9 cytoxins. Nature 20-l:99H. 1964 278. Starzl. T.E.: Tissue matching. In: The Puzzle People. Pittsburgh. 259. Starzl. T.E.. Marchioro. T.L.. Holmes. J.H .. Ht:rmann. G .. Brittain. University of Pittsburgh Press. 1992. pp. IIH-124 R.S .. Stonington. O.H .• Talmagt:. D.W .. Waddell. W.R.: Renal ho­ 279. Brent. L.: Immunogenetics: histocompatibility antigens: structure mografts in patients with major donor-recipient blood group incom­ and function. In: A History of Transplantation Immunology. Lon­ patibilities [addendum I. Surgery 55:195. 1964 don. Academic. 1997. pp. 153-15'1 2110. Starzl. T.E .. Ishikawa. M .. Putnam. C.W .. Porter. K.A.. Picache. R .. 280. Starzl. T.E .. Marchioro. T.L.. Terasaki. P.I.. Porter. K.A .. Faris. T.D .. Husberg. B.S .. Halgrimson. e.G .. Schroter. G.: Progress in and Herrmann. T.1 .. Vredevoe. D.L.. Hutt. M.P .. Ogden. D.A.. Waddell. deterrents to orthotopic liver transplantation. with special reference W.R.: Chronic survival after human renal homotransplantations: to survival. resistance to hyperacute rejection. and biliary duct re­ Iymphocytc-antigen matching. pathology and influence of thymec­ construction. Transplant. Proc. (): 129. 1974 tomy. Ann. Surg. 162:749. 1965 261. Rapaport. F.T .. Dausset. 1.. Lq!rand. L.. Barge. A. Lawrence. H.S .. 281. Terasaki. P.1.. Vredevoe. D.L.. ~Iiekey. M.R .. Porter. K.A.. Marchi­ Converse. 1.M.: Ervthrocvtes in human transplantation: effects of oro. T.L.. Faris. T.D .. Starz\. TE.: Serotvping for homotransplanta­ pretreatment with ABO group-specilic antigens. J. Clin. Invest. -+7: tion. VI. Selection of kidne" donors for thirty-two recipients. Ann. 2202. I%H N.Y. Acad. Sci. 129:500. 1%11 262. T.:rasaki. P.1.. MarchiofO. T.L.. Starzl. TE.: Scm-typing 01 human 2S2. Rapaport. FT.. Lawrence. HS. Thomas. L. Converse. 1.M .. Tillett. Iymphocvt.: antigens: pr.:liminar\' trials on long-term kidnev ho­ W.S .. Mulholland. J.II.: Cross-n:actillns to skin hllmografts in man. mogralt SurVivorS. In: Histowmpatibilitv Testing. Washington. DC 1. Clin. Invest. -+/:2166. 1962 National Academy 01 Sciences-National Research Council. 1%5. pp. 2SJ. Daussct. 1.. Rapaport. FT.: The Hu-I wstt:m of human histocom­ XJ-% patibility. In: Human Transplantalion. Rapaport. F.T. Daussct. J.. 26.1. Kissmcwr-Niclsen. F .. Olsen. S.. P.:tcrson. V.P .. Ficldhorg. 0.: Hv­ cditors. Orlando. FL. Grune .I:: Stratton. l'illH. p. 369 peracuic rClection 01 kidncv allografts asweiated with prcexlsti~g 2S". Rapaport. FT.. Daussct. J.: Behavior of HLA-compatiblc and in­ humoral anubodies against dllnor c.:lls. Lancet 2:662. 1%1l compatible skin allogratts in human recipients prelmmul11zed with 21l4. Williams. G.M .. Humc. D.M .. Hudson. R.P .. Morris. PJ .. Kano. K.. pooled leukocvte extracts ohtained from randomly selected donors. \lilgrom. F.: "/lyperacute" rl'nal-homogralt rCJection in man. Transplantation 36:592. 19S3 'I. Eng!. J. \lcd. 27<1:611. I%H 285. Starzl. T.E.. Pllrtcr. K.A. ..-\ndres. G .. Halgrimson. CG .. Hurwitz. R. 2(,5. Starzl. T.E .. Lerner. R.A .. Dixon. F.J .. Cilllth. CG .. Brettschneider. Giles. G .. Tc:rasaki. 1'.1.. Pcnn. I.. Schroter. G.T.. Lilly. J.. Starkie. 782 World J. Surg. Vol. 24. No.7. July 2000

S.1 .. Putnam. CW.: Long-term survival after renal transplantation in ~99. Bach. F .. Hirschhorn. K.: Lymphocyte interaction: a potential histo­ humans: with special reference to histocompatibility matching. compatibilitv test in vitro. Science 1-13:813. 1964 thymectomy. homograft glomerulonephritis. heterologous ALG. and 300. Martinez. C'.. Shapiro. F.. Good. R.A: Essential duration of parabi­ recipient malignancv. Ann. Surg. 172:437. 1970 ~ osis and development of tolerance to skin homografts in mice. Proc. 286. Mickey. M.R .. Kreisler. M .. Albert. E.D .. Tanaka. N .. Terasaki. P.I.: Soc. Exp. BioI. Med. IO-l:25fi. 1960 Analysis of HL-A incompatibility in human renal transplants. Tissue 301. IIdstad. S.T .. Sachs. D.H.: Reconstitution with syngeneic plus allo­ Antigens 1:57. 1971 geneic ll[ xenogeneic hone marrow leads to specific acceptance of 287. Starzl. T.E .. Eliasziw. M.. Gjertson. M .. Terasaki. P.L Fung. J.J .. allografts or xenografts. Nature 307: 168. 19H4 Trucco. M .. Martell. 1., McMichael. 1.. Shapiro. R .. Donner. A: 302. Thomas. 1.. Carver. M .. Cunningham. P .. Park. K.. Gonder. 1.. HLA and cross reactive antigen group (CREG) matching for cadaver Thomas. F.: Promotion of incomp~tible allograft acceptance in rhe­ kidney allocation. Transplantation 64:983. 1997 sus monkeys given posttransplant antithymocyte globulin and donor 288. Starzl. T.E .• Demetris, AJ., Murase. N .. Ricordi. C. Trucco. M.: The enigma of graft acceptance. In: Thoracic Transplantation. Shumway. bone marrow. l. In vivo parameters and immunohistologic evidence S.1 .. Shumway, N.E., editors, Oxford, Blackwell. 1995. pp. 452-470 suggesting microchimerism. Transplantation 43:332. 1987 289. Starzl. T.E., Demetris, AJ., Trucco, M .. Ramos. H .. Zeevi. A. 303. Przepiorka. D .. Thomas. E.D .. Durham. D.M .. Fisher L.: Use of a Rudert, W.A, Kocova, M., Ricordi. C. I1dstad. S .. Murase. N.: probe to repeat sequence of the Y chromosome for detection of host Systemic chimerism in human female recipients of male livers. Lan­ cells in peripheral blood of hone marrow transplant recipients. cet 340:876. 1992 Am. J. Clin. Pathol. 95:201. 11)91 290. Starzl. T.E., Demetris. A.1 .. Trucco. M., Zeevi, A, Ramos. H .. 304. Lawrence. H.S.: Homograft sensitivity: an expression of the immu­ Terasaki. P .. Rudert. W.A. Kocova. M .. Ricordi. c.. I1dstad. S .. nologic origins and consequences of individuality. Physiol. Rev. 39: Murase. N.: Chimerism and donor-specific nonreactivity 27 to 29 811. 1959 years after kidnev allotransplantation. Transplantation 55: 1272. 1993 305. Medawar. P.B.: The immunology of transplantation Harvey Lect. 291. Starzl. T.E .. Demetris. A1.. Trucco. M .. Ricordi. C. I1dstad. S .. 52: 144. 1<)56-1957 Terasaki. P.L Murase. N .. Kendall. R.S .. Kocoua. M .. Rudert. W.A. 306. Zinkernagel. R.M .. Doherty. P.C: Restriction of in vitro T cell­ Zeevi. A. Van Thiel. D.: Chimerism after liver transplantation for mediated cytotoxicity in lymphocytic choriomeningitis within a syn­ type IV glycogen storage disease and type I Gaucher's disease. geneic or semi-allogeneic system. Nature 2-1S:701. 1<)74 N. Engl. 1. Med.328:745. 1993 307. Zinkgernagel. R.M.: Restriction by H-2 gene complex of transfer of 292. Demetris. A1.. Murase. N .. Starzl. T.E.: Donor dendritic cells after cell-mediated immunity to Listeria monocytogenes. Nature 25/:230. liver and heart allotransplantation under short-term immunosup­ 1974 pression. Lancet 339: 1610, 1992 308. Doherty. P.C. Zinkernagel. R.M.: A biological role for the major 293. Dt:metris. A1.. Murase. N., Fujisaki. S .. Fung. J.1 .. Rao. AS .. Starzl. histocompatibility antigens. Lancet 1:1406. 1975 . T.E.: Hematolymphoid cell trafficking. microchimerism. and GVHD 309. Zinkernagel. R.M .. Dohertv. P.C: The discoverv of MHC restriction. reactions after liver. bone marrow. and heart transplantation. Trans­ Irrlmunol. Today 18: 14. 1997 . plant. Proc. 25:3337. 19?3 310. Zinkernagel. R.M.: Immunology taught hy viruses. Science 271:173. 294. Oian. S.. Demetris. A1.. Murase. N .. Rao. AS .. Fung. J.1.. Starzl. 1996 T.E.: Murine liver allograft transplantation: tolerance ;nd donor cell 311. Zinkernagel. R.M .. Ehl. S .. Aichele. P .. Oehen. S.. Kundig. T.. Hen­ chimerism. Hepatology 19:916. 1994 gartner. H.: Antigen localization regulates immune responses in a 2<)5. Murase. N .. Starzl. T.E .. Tanabe. M.: Fujisaki_ S.. Miyazawa. H .. Yeo dose- and time-dependent fashion: a geographical view of immune 0 .. Ddaney. CP .. Fung. J.1 .. Demetris. A.J.: Variable chimerism. graft wrsus host disease. and tolerance after different kinds of cell reactivity. Immunol. Rev. 156: 199. 1997 and whole organ transplantation from L..:wis to brown Norwav rats. :112. Starzl. T.E .. Rao. AS .. Murase. N .. Fung. 1.. Demetris. AJ.: Will Transplantation 60: 158, 1995 . xenotransplantation ever be feasible? J. Am. Coil. Surg. 186:383. 2%. Michi..:. D .. Woodrutf. M.F.A. Z..:iss. I.M.: An investigation of im­ 1998 munological tolerance based on chimera analvsis. lmmu-nologv -1:413. 313. Sterzl. J.. Silverstein. AM.: Development aspects of immunity. Adv. 1961 .~. Immunol. 6:337, 1967 21)7. Simonsen. M.: Graft versus host reactions: their natural historv. and J 14. Matzinger. P.: Tolerance. danger. and the extended family. Annu. applicabilitv as tools of research. Prog. Alkrgv ():J~9. 1962 . Rev. Immunol. 12:<)<)1. 1<)9~ 21)S. Bain. 13 .. Vas. M.R .. Lowenstein. C.: The -j..:vclopment of large .\ 15. Ridge. l.P .. Fuchs. E.J .. Matzinger. P.: Neonatal tokrancl.! revisit..:d: Immature mononuclear cells in mixed kukocvtc cultures. Blood turning Oil newborn T cells with dendritic cells. Science 27/:1723. 23: IOH. 1964 . 1996