J!)5J

Surgery: Basic Science and Clinical Evidence, " 1379-1401, 2001.

A History of Clinical Transplan ta tion Thomas E. Starzl

Prehistory: Before Immunosuppression ...... 1380 Immunologial Screening ...... 1390 The Concept of ImmunosuppressIOn ...... 1382 Allograft Acceptance Versus Acquired Tolerance .... 1391 The Maturation of Transplantation...... 1387 Conclusion...... 1394 The Ripple Effect ...... 1388 References ...... 1395

OW transplantation came to be a clinical discipline cattle Ithe calf equivalent of human fraternal [dizygotic] Hcan be pieced together by perusing two volumes at twins) became permanent hematopoietic chimeras if fusion reminiscences collected by PaulL Terasaki in 1991- of their placentas existed in utero, allowing fetal cross-circu­ 1992 from many of the persons who were directly involved. lation (Fig. 61.1); such animals permanently accept each One volume was devoted to the discovery of the major his­ other'S skin. I2 Burnet and Fennerl3 predicted that this nat­ tocompatibility complex (MHC), with particular reference to ural chimerism and tolerance to other donor tissues and or­ the human leukocyte antigens (HLA) that are widely used to­ gans could be induced by the kind of experiments success­ day for tissue matching. l The other was focused on mile­ fully performed by Billingham, Brent, and Medawar. However, stones in the development of clinical transplantation.2 All the Billingham and Brent I4,15 soon learned that in mice, parallel contributions described in both volumes can be traced back with similar observations by Simonsenl6 in chickens, the in one way or other to the demonstration more than a half penalty for infusion of immunocompetent hematopoietic century ago by Peter Brian Medawar that the rejection of al­ cells was graft-versus-host disease (GVHD) unless there was lografts is an immunological phenomenon.3,4 a close genetic relationship (i.e., histocompatibility) between Ten years later (1953), Billingham, Brent, and Medawars the donor and recipient. showed that tolerance to skin allografts could be induced by This discovery was the beginning of modern transplanta­ inoculating fetal or prenatal mice with immunocompetent tion immunology, an extensive history of which has been spleen cells from adult donors. Because of their immunolog­ written by Brent,I7 one of its principal architects. Each cell­ ical immatunty, the recipients were incapable of rejecting the and organ-defined branch of transplantation also has had its spleen cells whose progeny survived indefinitely. Specific historians, who have described the stages through which spe­ nonresponsiveness to donor strain tissues was retained as the cific kinds of procedures moved to the bedside from experi­ recipient animals grew to adult life, while normal reactivity mental laboratories, or in some cases directly. The culmi­ evolved to third-party grafts and other kinds of antigens. nating clinical events can be capsulized with a list of the first This was not the first demonstration that tolerance could successful allotransplantation, in humans, of the kidney, 18 be deliberately produced. Analogous to the neonatal trans­ liver,19 heart,2o,21 lung,22 pancreas,23 intestine,24 multiple ab­ plant model, Traub6 showed in 1936 that the lymphocytic dominal viscera,25 and bone marrow.26- 29 choriomeningitis virus ILCMV) persisted after transplacental Although such milestones and dozens of lesser ones are illiection of the embryo from the mother, or alternatively by important, the emphasis in this account is on developments In]ection into newborn mice. However, when the mice were that were applicable to all varieties of allografts and respon­ ~ntected as adults, the virus was eliminated immunologically. sible for major transitions in transplantation ideology. It lmllar observations had been made in experimental tumor will become apparent as the layers of history are peeled away ~odels. Murphy 7 reported in 1912 the outgrowth of Rous that there were only two seminal turning points in the evo­ ~ leken sarcoma cells on the chorioallantoic membranes of lution of clinical transplantation. One was the induction of lick or pigeon egg embryos, which could be reversed by in­ chimerism-associated neonatal tolerance by Billmgham, Brent, OCUlatIOn of auult chicken lymphoid cells 8 whereas sarcoma and Medawar in 1953. The second was the demonstration in lib 1 . . ' P antatlOn mto adults was not possible. 1962-1963 that organ allografts could self-mduce tolerance the The observations of Murphy and Traub did not influence with the aid of immunosuppression. 30 All subsequent devel­ ttl early development of transplantatIOn. Instead, the Impe­ opments in organ transplantation depended on exploitation ~ and rationale for the experiments of Billingham, Brent, of this principle, using variations of the drug strategy that had anOng Medawar,5,9. and similar studies in chickens by Hasek, !O made its discovery possible. Ironically, the downside of the mated With Owen, II who demonstrated that freemartin resulting revolution in organ transplantation was the early in-

1379 1380 CHAPTER 61

Corpus luteum worked out mainly with the kidney and liver and .' ill R. ovary G ?[J}. L oVary other organs with minor modificatlOns. applied to 'ilerr Red cell JI ~'" Red cell ~itallIl o Type I A~..._ ".;~ (. ') Type II Tht ----!~~ -"""'Sj;- \'iSltOr~ '~)V C • '0 Hetero (Xeno) Transplantation ).~ :i?1-i---, iro il1 tl The first known attempts at clinical renal transplantatio (oneal /., :;'1r I I vascular anastomoses were made between the begin . n by Europe ) the nineteenth century and 1923 in France,-l7 German~g of senbec elsewhere (summarized by Groth-l9 ) using pig, sheep, :d I gO~t ter Ber subhuman primate donors. None of the kidneys funet" d I . . . loned ever, J I for long, 1£ at all, and the human reCIpients died a few h I . Ours thigh, to 9 days later. No further ammal-to-human transplantat with \ Y were tried again until 1963, after immunosuppression ~ns 11 available.50,51 as OType II ( one. ,oJ oryp. I SpriIli Homo (Allo) Transplantation Dooli ::. ReCIPrOC:1 ::;::- 'l'n::;ijl:::.... o noma tolerance ~J) to skin graft In 1936, Voronoy of Kiev, Russia, reported the transplanta. fossa .... tion of a kidney from a cadaver donor of B+ blood type to a recip FIGURE 61.1. The chimerism in freemartin [fraternal twins) de­ recipient of 0+ blood type,52. in violation of what have be­ theE scribed by Owen.ll Cross-tolerance to formed blood elements fol­ come accepted rules of tissue transfer53,5-l (Table 61.1). In ad. State lowed intrauterine circulatory exchange in dizygotic twins. Mutual dition, the allograft was jeopardized by the residual risk of mod: tolerance to skin grafts was later proved by Anderson with Medawar et a1. 12 [From Starzl TE) Blitz GW JI. Surgical physiology of the trans­ acute mercury poisoning (from a suicide attempt) that caused Moo plantation of tissues and organs. By permission of Surg Clin North the recipient's renal failure. A final adverse factor was the 1 Am 1962;42:55-67.) 6-h lapse between the donor's death and organ procurement. plac' The allograft did not make any urine during the 48 h of the Hun troduction of a conceptual error that distorted the maturation patient's posttransplant survival. Although other attempts 195: of transplantation immunology and also adversely affected may have been made by Voronoy,55 another 15 years passed ieal the orderly development of general immunology. before significant kidney transplant activities were resumed din The error, which was not corrected until well into the in France. unt: 1990s,31~33 was the conclusion by concensus that organ allo­ In 1951, Rene Kuss56 and Charles Dubost57 in Paris and the graft acceptance involved different mechanisms than the Marceau Servelle in Creteil,58 carried out a series of renal casl chimerism-dependent ones of neonatal tolerance and its clin­ transplantations with kidneys removed from convict donors Dal ical analogue of bone marrow transplantation. Consequently, immediately after their execution by guillotine. The next la·' the vast literature that sprang up in the intervening 30 years year, the French nephrologist, Jean Hamburger) in collabora· tiel admirably documented the progression of improvements in tion with the urologist Louis Michon at the H6pital Necker eXl clinical transplantation while failing to explain what was be­ in Paris, reported the mother-to-son transplantation of a kid· pri ing accomplished.34 Therefore, the reader may profit by skip­ ney that functioned well for 3 weeks before being rejected. 59 erG ping to the last section of this chapter ("Allograft Acceptance The procedure developed by Kuss and the other French sur­ Versus Acquired Tolerance") before attempting to understand geons and used for this first live donor kidney transplanta­ ea: what went on between 1963 and 1993, and before. tion has been performed hundreds of thousands of times since co then. The operation's relative freedom from chronic morbid­ id, ity would soon be demonstrated with the identlcal(monozy­ pr Prehistory: Before Immunosuppression gotic) twin transplantations of Joseph E. Murray and John ic in An indelible mark on the pages of transplantation history was pJ left with the perfection of techniques for organ revascular­ l' ization by surgical anastomosis in the laboratories of Alexis TABLE 61.1. Direction of Acceptable Organ Transfer When the 11 Carrel at the beginning of the twentieth century.35 Aside from Donor and Recipient Have Different ABO Red Cell Types. the technical contributions, which also provided the founda­ o to non-O Safe c tion for conventional vascular surgery, Carrel recognized that Rh- to Rh+ Safe transplanted organ allografts were not permanently accepted Rh+ to Rh­ Relatively safe although he did not know why. A to non-A DangerOuS Using vascular surgical techniques, animal research in B to non-B DangerouS transplantation was most highly focused on the kidney for AB to non-AB Dangero~ most of the next half-century.36-38 The extrarenal vacuum rapidly was filled between 1958 and 1960 with the develop­ ment in several laboratories of canine models with which to study all the intraabdominaP9--+3 and thoracic organs 4 4-46 AI· though each organ presented specific technical and physio­ logical issues, the core problems of immunosuppression! tis· sue matching, and allograft preservation eveRtually were • A HISTORY OF CLINICAL TRANSPLANTATION 1381

J heir associatesC,o at the Peter Bent Brigham Hos­ The existence of these cases was public knowledge, but aJlll t the failure of all the grafts (usually with death of the patients) . Boston. 'd 1 I 1 U1 'f bv the: French teams were WI e y

TABLE 61.2. Nobel Prizes Related to Immunology/Transplantation.

1901 Emil Adolf von Behring Discovery of antibodies 1905 Hemrich Hermann Robert Koch Cause and effect of microorganisms and infection the t 1908 Paul Ehrlich Side-chain (receptor) concept; champion of humoral tOlera antimicrobial therapy there \~t llya Metchnikoff Champion of cellular immunity. chin 1912 Alexis Carrel Vascular surgery and transplantation Jogs in ' 1919 Jules Bordet Discovery of complement good rer 1930 Karl Landsteiner Discovered ABO blood group antigens cipieut atol 1960 Sir Frank MacFarlane Burnet Clonal selection hypothesis be!l1 Sir Peter Brian Medawar Acquired transplantation tolerance before d that thi: 1972 Gerald M. Edelman Characterized immunoglobulins Rodney R. Porter Clanfied structure of antibody molecule lyJIlpho waS sus 1980 Barui Benacerrat Discovered immune response genes and collaborated in discovery of MHC restriction elperin Jean Dausset Discovered first HLA antigen paport ' George Davis Snell Discovery of major histocompatibility complex (MHCj gene in .' tOlUCor 1984 Niels Kai rerne Important immunological hypotheses ~,. a[ bod: Georges r.F. Kohler Hybridoma technology "', . Cesar Milstein Hybridoma technology BoNE I 1985 Michael Stuart Brown Hepatic control of cholesterol metabolism (With Goldsteinl' Joseph Leonard Goldstein With t t!ansp 1987 Susumu Tonegawa Discovered somatic recombination of immunological receptor genes planta 1988 Gertrude Belle Elion Codiscovery iwith Hitchings) of 6-mercaptopurine (6-MPI and associ azathioprine by Bit' George Herbert Hitchings spite ( 1990 Joseph E. Murray Kidney transplantation be us E. Donnall Thomas Bone marrow transplantation was a 1996 Rolf Zinkernagel Codiscovered (with Doherty) the role of MHC tient in adaptive immune response to pathogens ting , Peter C. Doherty Fi "Proved with liver transplantation for indicatlOn oi hyperchoiesteroiemia."9,25o a1. at man' of 11 secreted identical antibodies (the clonal selection theory). but also the most important clinical advances in transplan­ Hon Nossal subsequently proved that the clone rose from a single tation of the succeeding decades. First, skin grafts exchanged then cell ("one cell/one antibody")?! Although Burnet's hypothe­ between l-day-old chicks of different breeds had a high rate ligm sis was not yet complete, it was to become the cornerstone of initial engraftment and a 6% incidence of permanent take. end' of modem immunology. Second, the window of neonatal opportunity was gone by 4 men days. Third, and most important, the percent of permanent 1 engraftment of neonatally transplanted skin was increased to ltsc The Concept of Immunosuppression more than 20% by a course of cortisone, with no increase of expl mortality. quiJ war With Recipient Cytoablation The significance of the third observation was recognized by Cannon and Longmire, who wrote: "Although the co~' The transition of tissue and organ transplantation from an ex­ sane did not entirely prevent a reaction in the homograft, It ~rcise in futility to tenuous practicality involved a surpris­ did decrease the incidence of reaction. Even more importan~ ngly small number of advances that were interspersed with the increased incidence of reaction (sic) free grafts appeare ong periods of frustration. Alter Medawar's demonstration in to maintain itself after the drug was discontinued. This phe­ 1944 that rejection was an immunological event,3,4 a logical nomenon is one which up to the present time has not bee~ md inevitable question was, why not protect the organ allo­ found in homograft experiments on mammals and humans. ;raft by weakening the immune system? This idea was tested Despite a confirmatory follow-up study in 1957/3 the n~­ n rabbits in 1950-1951 with cortisone63.64 and total-body iI­ glected Cannon-Longmire article faded quickly from the co . adiation72 Both prolonged skin graft survival for only a few lective memory of both basic scientists and cliniCians. In co:­ ays. trast, the achievement of acquired neonatal tolerance Y 1 Neither these results, nor those reported with cortisone Billinbo-ham. Brent, and Medawar in 1953 5.9 ignited mterest Ul M' an d 1 1952 by Cannon and Longmire65 in a chicken skin graft transplantation as never before. Two years later, aln t lOde!. generated much optimism. However. the Cannon­ Prehn74 attempted to simulate in adult mice the environrnerr ongmire report contained three observations that, in retro­ that allowed the acquisition of neonatal tolerance. The thr~~ iect, presaged not only the acquired neonatal tolerance pro­ steps were first, to cripple the immune system with 5U:~. .Iced by Billingham, Brent, and Medawar the following year, lethal total-body irradiation ITBIJ i next, to replace It Wit

. ..:.,.. A HISTORY OF CLINICAL TRANSPLANTATION 1383

marrow (producing a hematolymphopoietic WHOLE-ORGAN TRANSPLANTATION b:; iinally, to engraft skin from the same inbred In contrast, clinical organ transplantation, which preceded h' donor ot the bone marrow. bone marrow transplantation by a decade, appeared to be dis­ ... as t C rim were successful/4 but as in the neona- ents connected from a rational base when it was concluded that .. The exyemodel, lethal GVHD could be avoided only when organ engraftment seemingly was independent of chimerism. 70 o· rolerance"weak" histocompatibility barriers. . Applying ~ An extension of the Mam-Prehn strategy (i.e., lethal TBl fol­ . .'... Iller.. - were . m strategy tor. l'(1 d ney transp1'· antatlOn m b eagI e -hnnens . 76 d lowed by bone marrow and kidney allografts as in Mannick's thee Cooperstown, New York, Manmck et a1. ' reporte dog) was used by Murray et al H2 in only 2 cases, both in 1958. dog:> In 1 llograft tunctlOn m a supralethally uradiated re- _vi rena a. d The next 10 kidney recipients in Boston were conditioned 'P'.¥ hat also was given donor bone marrow an was a 18 t with sublethal TBl without bone marrow ,82,B3 Eleven of Clplen It'mphopoietic chimera; the animal lived for 73 days the 12 irradiated patients died after 0 to 28 days. \ng of pneumonia. Because it was demonstrated later heIllat~ The survivor (who was not given bone marrow) had ade­ betor~ Ykind of outcome depended on the identity of the dog quate renal function from the time hiS fraternal twin brother's that th antigens (DLAI, 77,78 an accidental DLA match l~vte kidney was transplanted on January 24, 1959, until he died lymP °p~cted in retrospect to have been present in Mannick's was SUS ~ in July 1979 (Table 61.3). With this historical accomplish­ 9 expen·ment . Efforts by Hume et a1.7 and subsequently by Ra-. ment, the genetic barrier to organ transplantation had been . t80 and others to broaden the range of acceptable hlS- definitively breached for the first time in any species. 18 Five ;!o:omPJnbilitY inevitably led to lethal GVHD, rejection, 84 ice months later, Hamburger et a1. added a second fraternal or borh. twin transplantation, using the same treatment (Table 61.3). This second recipient had good renal function until his death BoNE MARROW TRANSPLANTATION 26 years later from carcinoma of the urinary bladder. With the impasse, workers in bone marrow and whole-organ In these two dizygotic twin cases, it was conceivable that transplantation took separate pathways. Bone marrow trans­ the donor and recipient placentas had fused dunng gestation, plantation was dependent a priori on the classic chimerism­ analogous to Owen's freemartin cattle (see Fig. 61.1). This sus­ associated acquired tolerance induction defined at the outset picion was put to rest at the Paris centers of Jean Hamburger85 by Billingham, Brent, and Medawar in the neonatal model. In and Rene KUSS 86 by four more examples during 1960-1962 of spite of the fact that only highly histocompatible donors could survival of 1 year or more. In Kuss' two cases, the donors were be used, clinical success with bone marrow engraftment not related (see Table 6l.3). During the critical period from was achieved in 1963 by Mathe et al. in Paris,26 whose pa­ January 1959 through the spring of 1962, the cumulative tient lived for 2 years with chronic GVHD before commit­ French experience was the prinCipal (and perhaps the ody) jus­ ting suicide. tification to continue clinical trials in kidney transplantation. Five years later, Gatti et a1. in Minneapolis28 and Bach et The experience from Boston and Paris summarized in al. at the University of Wisconsin,17 each transplanted bone Table 61.3 showed that bone marrow infusion was not a nec­ marrow to recipients who are well today. The lifetime efforts essary condition for prolonged survival of kidney allografts of Thomas,29 van Bekkum,sl and others fueled the matura­ and ostensibly eliminated the requirement of chimerism. The tion of bone marrow transplantation into accepted clinical stage was set for drug therapy. In fact, both Hamburger and therapy for numerous hematological diseases (including ma­ Kuss mentioned the use of adrenal cortical steroids as an ad­ lignancies), acquired immunodeficiency disorders, mes­ junct to TBI (Table 61.3), but neither the dose, nor the indi­ enchymal-based inborn errors of metabolism, and an assort­ cation for the steroids, was described. In addition, Kuss sec­ ment of other indications. ondarily administered 6-mercaptopurine (6-MP) to one of his Bone marrow transplantation was an intellectual triumph. cytoablated patients as early as August 196086 "on the basis Its development could be traced in a straight line back to the of the recent results of the experimental studies conducted experiments of Main and Prehn 74 and before that to the ae­ by CaIne ... "87 (see next section). Calne had made an invited qUir:d neonatal tolerance of Billingham, Brent, and Meda­ visit to the Paris center a few months earlier (Rene Kuss and War) 9 and the natural tolerance of Owen's freemartin cattle. ll Roy CaIne, personal communication).

TABLE 61.3. Kidney Transplantation with 6 Months or More Survival as of March 1963. Survival Cnse City" References Date Donor (months)b Boston 18,82,83 1-24-59 Fraternal twin >50 Paris 84,85 6-}9-59 Frarernal twin >45 3 Paris 86 6-22-60 UnrelatedC 18 (diedl 4 Paris 85 12-19-60 MotherC 12 (died) Paris 86 3-12-61 UnrelatedC 18 (died) 6 Paris 18 }-12-62 Cousinc >13 Boston 83, lOS 4-5-62 Unrelated 10

"Boston: I.E. Murray Ipatients 1, 7l; Pans: r. Hamburger Ipatlents 2, -t, 6!; R. KU5S ,patIents 3, 51.

hThe kidneys in patients 1, 2, and 6 tunctioned for 20.5, 25, and 15 years, respectively. Pdtient 7 reiected his graft af­ ter 1'" months and died ~liter return to Jialy:-;is. <.;AJlunct sterolu therapy. 1384 CHAPTER 61

Some authOlities have considered irradiation-induced and was recognized. CaIne and Murray also were fore .....•. drug-induced graft acceptance to be different phenomena.49,83,88 an earlier climcal experience of .Hopewell, Caine, an~;~ed.hy.;:' More recently, it has become obvious that the variable degree et al., lOJ which was not pubhshed until 1964 in hS\Vick of graft acceptance achieved with sublethal TEl between Jan­ MP had been used to treat three kidney recipie~ts (iW tch 6- uary 1959 and February 1962 was fundamentally the same as one with a live donor) in 1959-1960; all three recipinc Uding that seen in tens of thousands of drug-treated humans fol­ died. ents had lowing transplantation of various whole organs (see later, "Al­ Consequently, the canine studies of 6-MP and , " aZathiO- lograft Acceptance Versus Acquired Tolerance"). pnne 111 Boston were hIghly focused on finding more ff tive drug combinations,83,9:i,97,104 Although d e ,ee. a renoCOrtIcaj steroids were tested, they did not appear to potentiat th With Drug Immunosuppression value of azathioprine,95,97 prompting Murray in his die, ale After it was leamed that TEl alone could result in prolongation tna. 1 to opt f or a d'Junct CytotOXiC. agents suc h as azaserinerue d of kidney allografts, it was logical to focus the search for im­ actinomycin C. 83 Only 1 of the first 10 kidney recipiean munosuppressive drugs on myelotoxic agents that mimicked treated with either 6-MP in = 2) or azathioprine-based ~t~ irradiation. In September 1960, Willard Goodwin of Los An­ munosuppression (n = 8) survive~ for more than 6 mon:s Brighar geles produced severe bone marrow depression with metho­ (the last entry in Table 61.3),83,100 john ~ trexate and cyclophosphamide in a young female recipient of At the nadir of the resulting pessimism, two reproducible Willarc her mother's kidney. The patient subsequently developed sev­ observations, first in dogs and then in humans, were made at cause 2 eral rejections that were associated with bone marrow re­ the University of Colorado. Taken together, these events pro­ total b( covery. They were temporarily reversed with prednisone sev­ foundly shaped future developments in transplantation of all at the 1 eral times during the 143 days of survival. It was the first organs, and eventually of bone marrow. The observations Kuss, ' example of protracted human kidney allograft function with were encapsulated in the title of a report published in Octo­ ing az: drug treatment alone.89 However, the case was not reported ber 1963: "The Reversal of Rejection in Human Renal Ho. Th until 1963. mografts with the Subsequent Development of Homograft an exa Tolerance. "30 duce' The reversal was readily accomplished by temporarily create adding unprecedented high doses of prednisone (200 mg/day) ney tr to baseline immunosuppression with azathioprine. The evi­ in EUl dence that the live donor kidneys had self-induced tolerance in opt Tl under an umbrella of immunosuppression was equally dear. Most of the recipients had a subsequent progressively di­ prom these minishing need for immunosuppression, usually to doses mun( lower than those that initially failed to prevent rejection. The tolerance was complete enough to allow the patients to go m~ I home to an unrestricted environment, Nine of the first 10 of cept~ from these kidney recipients achieved prolonged graft survival,JO mou: including two who bear the longest continuously function­ surv' ing allografts in the world today (more than 35.5 years) and prod have been free from immunosuppression for 32 and 4 years, respectively. 106 was The practical as well as theoretical implications of these thor observations were recognized throughout the report: "A state was of relative immunologic non-reactivity seems to have been of a produced which has lasted for as long as 6 months , .. It is had not known whether this is due to a change in the antigenic and properties of the homograft, or to an alteration in the specific the [host) response to the stimulus of the grafted tissues. The ap­ tim parent host-graft adaptation does, however, provide some tral hope for prolonged functional survival .. , It would seem prob­ day able that the [therapeutic) principles, as defined with the kid­ ney, can eventually be applied to other organ homografts .. ' ME The prior knowledge that a rejection crisis is almost a cer­ ab( tainty and that it usually can be managed by relatively con­ thl servative means should serve as a deterrent to the excessive 1,( use of measures that may cause fatal bone marrow depres­ co sion .. , It is also conceivable that the avoidance of a primary D, host-graft reaction by these means [excessive Immunosup- tir pression) would prevent the adaptive process If ;0 de At the time this bellwether series was comptled between the autumn of 1962 and April 1963, the only other active clin­ ical transplantation programs in the United States were In ·c th Richmond (dnected by David Hume)107 dnd at the Peter Bent A HISTORY OF CLINICAL TRANSPLANTATION 1385

E!I1ptrca. I Therapeutic Dogma of Immunosuppression. an adaptation of some kind ... a possibility Woodruff has long Baseline agents urged us not to overlook [110,1111 though there is no reason " of strategy~ ______to believe it an antigenic adaptation". . ~ AzathIOprine" lin" therapy C 1 . Medawar continued 109: "One possible explanation is the ~ . adjustments yc osponne progressive and perhaps very extensive replacement of the , ' 5e'onJ~lIsone dose, or vascular endothelium of the graft by endothelium ot host ori­ , of pre hoiJ agentsb : Jl1ulyITlP . Tacrolimus gin, a process that might occur insidiously and imperceptibly , , .w·case trial I during a homograft reaction weakened by immunosuppres­ . CJSc J oren tial eno r [;Ill P sive drugs ... Another possibility, raised by R.Y. Caine . I wean 109 . . ~hylactiC prednisone. Equivalent results were obtamed with (though not mentioned by him in his contribution to this vol­ 'Alone or With P~~PmsteaJ of azathioprine. l73•ll• ume) is the laying down of a protective coat of host antibody Jophosphaml . 1/" 11136 eye , d for praphyiacllc rnductwn. on the endothelial inner surface of the graft ... an explana- llJUuallv use tion which would classify the phenomenon under the general heading of 'enhancement'. " . am Hospital in Boston (directed by Joseph Murray an~ These disclaimers notwithstanding, the commonality of Bngh Mernll). 105 The hIstorically important program ot the rejection barrier for different organs was self-evident. So IO~ll d Goodwin at UCLA isee earlier89) had been closed be- was the likelihood that the means of inducing acceptance of Wi ar the recipients dIed.. m less t h an 5 monthIE s. n urope, cause aII .' f d one organ could be used for all the others. 112 There also was 1b dy irradiation bneHy remamed the pre erre treatment rota 0 d R evidence from earlier experiments that a liver allograft could h long-standing Paris centers of Jean Hamburger an ene Jtt e '. db protect other donor tissues and organs. It had been noted m Kuss, while Michael Woodrutf of Edmburgh ha egun test- 1962 that intestine and pancreas had very little histopatho­ · . 108 ing azat hlOpnne. . . logical evidence of rejection in untreated canine recipients if The results in the Colorado senes, and more Importantly they were components of multivisceral allografts that also an exact description of the strategy that had been used to in­ included the liver.113 The observations were confirmed 30 duce variable degrees of incomplete tolerance (Table 61.4), years later in a rat version of the same multivisceral proce­ created a surge of new activity. Within 12 months, new kid­ dures1l4.115 ney transplant centers proliferated in North America, and also Most convincingly at an experimental level, it was shown in Europe. Most of these second-generation programs remain in 1964 that orthotopic canine liver allografts could induce in operation today. and maintain their own acceptance far more frequently and The observations in the original kidney recipients were permanently than renal allografts, even with a treatment promptly confirmed. However, the proposed explanation for course of azathioprine as short as 4 months. I 16,117 Soon tllere­ these successes (i.e., graft alteration plus loss of specific im­ after, spontaneous engraftment was demonstrated after liver munological responsiveness)30 was controversial and re­ transplantation in untreated outbred pigs,llB-122 many of mained so for the next three decades (see later, "Allograft Ac­ which passed through self-resolving rejection crises. 121 ,123.124 ceptance Versus Acquired Tolerance"). Except for reports Thus, it already was clear by 1964-1965 that the liver is from the University of Colorado, the term tolerance was stu­ the most tolerogenic organ. In the late 1960s and early 1970s, diously avoided from 1964 onward in referring to the long­ CaIne, Zimmerman, and Kamada formally proved that the surviving dogs and human kidney recipients that had been liver tolerization extended to other donor tissues transplanted produced by the end of 1963. at the same time or later, first in untreated outbred pigsl25 The article most often quoted as contravening tolerance and then without immunosuppression in selected rat strain was that of Murray et a1.102 despite the fact that, as the au­ combinations.126-128 Although they were important, the ex­ thors took pains to make clear, the evidence in their report perimental studies with hepatic allografts only affirmed the was inconclusive and mvolved only two canine experiments conclusion reached with the 1962-1963 experience in clini­ of a potentially crucial nature. The two long-surviving dogs cal renal transplantation suggesting that all organs were ca­ had been given renal homografts 9 and 18 months previously pable of inducing tolerance. Just as with liver allografts, the and had been treated for most of these periods with one of self-induction of donor-specific tolerance by heart and kidney the purine analogues. Renal function was deteriorating at the allografts without the aid of immunosuppression was later tIme contralateral kidneys from the original donors were demonstrated by Corry1l9 and Russell l30 in selected mouse t.ransplanted. The second organs were rejected after 23 and 3 strain combinations. days, respectively, as would be expected. The key mechanism of kidney induced allograft accep­ In commending Murray's 1964 report and conclusions, tance was suggested as early as 1964 to be clonal exhaus­ !VIedawar wrote 109:. "There is, however, something special tion.lJ! This concept was developed more fully for liver al­ about renal homografts, as [Michaell Woodruff's appraisal in lografts in the illustration and caption reproduced in Fig. 61.2, thIS volume makes very clear. A synoptic survey of more than published in 1969. 132 Induction of the activated clone by al­ 1,000 renal homografts in dogs carried out by Murray and his loantigen was depicted via host macrophages rather than by ~lIeagues IMurray, Ross Sheil, Moseley, Knight, McGavic &. antigen-presenting dendnuc cells, which would not be de­ ,al11mlU, 19M I [102] has shown that foreign kidneys do some­ scribed until 1973 133 In the text accompanying the figure, it tll11es become acceptable to theH hosts for a reason other than was pointed Out that exhaustion and deletion of an antigen­ acqUired tolerance in the technical sense ... There has been specific clone had been postulated by Schwartz and Dameshek as early as 1959 to be the mechanism of the tol­ erance to heterologous protein induced in rabbits with the aid ;~n~Inaj nurnbt:!rs' I cham:;ed to those of current reference list (this chapteri; t: qUOtation IS uthtrwise verbann1. of 6-mercaptopurine.90 In additIOn, Simonsen had suggested 1386 CHAPTER 61

water Tissue Electrolytes most ( Lymphocytes lSerum proteins carini] ~ Humoral antibodies role of llC )ll -( den (/~ oJ «.welD ahead. Anti::~roPh~~_~f\IJ B.~ I \ ~ , '(.----.0 The Lymphocytes ~----\-*3 Altho (t/!) ~~ ~ \~ ~ requlI ~ .------. ~ ~ ~-----L- Top view Cross sec tion (9l • ~ (Ij! II!il ~ ~ /II) .• 1< ~ .rj> I#) ~ 5enti~ FIGURE 61.3. Schematic representation of diffusion chamber used in studies by Algire,144 from which he concluded that lymphocytes ther t S~:~~:i:n ¥~}~~~-~~=~~K~~T~~~~~l~E were the cellular agents of allograft rejection. (From Starzl TE, Butz in wi I \ GW Tr. Surgical physiology of the transplantation of tissues and or­ reliat 1m rriunoglobulins gans. By permission of Surg Clin North Am 1962;42:55-67.) mune FIGURE 61.2. Hypothesis published in 1969 of allograft acceptance vatio by clonal exhaustion. Antigen presentation was depicted via the simism also was deeply ingrained in conventional practi­ plant macraphages rather than by the dendritic cells (which had not yet been described). A gap in this hypothesis was the failure to stipulate tioners of medicine. Well into the 1960s editorials were pub­ mine the 10catlOn of the immune activation. (By permission at Experience lished in major clinical journals that questioned both the in­ stallt in Hepatic Transplantation. W.B. Saunders Co., 1969. 132 ) herent feasibility and the ethical basis of transplantation term procedures. 147 As a consequence, transplantation acquired a impr renegade image, a burden soon compounded by difficulties in jectil in 1960 that clonal exhaustion induced by allogeneic spleno­ extending its reach to the replacement of vital organs other niso: cytes could lead to the acquisition of tolerance in adult ani­ than the kidney. mals in the absence of immunosuppression.134 One dilemma, as it was perceived at the time, is shown The error of making semantic distinction between toler­ in Figure 61.4.148 It was feared that chronic drug immuno­ Imt ance and graft acceptance was understandable. The picture suppression powerful enough to prevent organ allograft rejec­ ANl that had emerged from the remarkable accomplishments with tion would render the recipient hopelessly vulnerable tr: in­ clinical kidney transplantation between January 1959 and the digenous and enviromnental pathogens. Early reports of Ben spring of 1963 was not a product of new insight in immunol­ infectious disease complications in the early Colorado recipi­ ical ogy. Instead, successful organ transplantation was an intel­ ents149 and elsewhere, gave warning that dire consequences era] lectually troubling and inexplicable violation of the im­ might, in time, be in store for all recipients. It also was sus­ ".., . munological rules of the time. The revolution in immunology pected that immune surveillance to tumors would be eroded, mu that had already began, and would continue for the next third a possibility that was verified but shown to be manageable by due of a century, did little to change this view. 1968.1S0~lS2 der The Burnet antibody hypothesis of clonal selection Isee Autopsy studies in failed clinical cases revealed a typical hac earlierl3 ) was validated and extended to cellular immunity by pattern. Infections for which specific antibiotics were avail­ the late 19505,135-137 but this had minimal influence on the able could be largely controlled. However, opportunistic mi­ 19( clinical development of transplantation; neither did many croorganisms of normally low pathogenicity were overrepre­ th, other key advances in immunology that were either contem­ sented and appeared at autopsy to be the main cause of m, poraneous with, or came after, the rise of organ transplanta­ death. 153 Of these infections, cytomegalovirus (CMVI was the tat tion. The role of the thymus in the ontology of the immune iec system and in the postnatal immune function of rodents was hu discovered in 1961 [by Jacques MillerI38,139). However, in hu­ Host defense H( mans thymectomy did not significantly alter either the early TI or late course of kidney transplant recipients. 140, 141 Lympho­ ly cytes were not formally assigned a function until 1963 (by m James Gowans 142, 143), although workers in transplantation ne wcre aware several vears earlier that these mononuclear cl leukocytes were the c~llular agents of allograft rejection 144~146 IFig. 61.3). By the time the distinction was clearly established SC between T and B lymphocytes, transplantation was an estab­ tr lished specialty of clinical medicine. fr Thus, the ascension of organ transplantation came as a i! surprise to most immunologists. Even as the clinical advances b had begun to unfold, Burnet!37 had wntten III the New Eng­ c Bacteria ~\1MUNOSUPPRESSION r land Journal of Medicme that, " ... much thought has been (peak at rejection crisis) Bacteria given to ways by which tissues or organs not genetically and FIGURE 61A. The original legend for thlS iigure was" PI ),sible mech­ " antigel11cally identical with the patient might be made to sur­ anisms of simultaneous loss of host reactivity to spcCllic straWS at vive and function in the alien enVlronment. On.the whole, endogenoLls bacteria, as well as to the alien renal tissue." [By per­ the present outlook lS highlY unfavorable to success .... ". Pes- miSSlOTI of Surgery :St. Louis) 1964;56:296.] A HISTORY OF CLINICAL TRANSPLANTATION 1387

mon and lethal. The presence of Pneumocystis the raw antilymphocyte serum (ALS) was administered. In J1Iost con: coinfection with CMVl54 premonitored the lethal preparation for clinical trials, horse antidog ALS was prepared, ,<'",rinJl .. ash's combinanon,',' ot mtecnous . agents m . t I1e AIDS epI-' and the active moiety was refined from the gamma globulin. ISS I at t 1 !1l e. . the non transplant population that lay two decades After the product was shown to inhibIt or reverse rejection in deIlllC In the canine kidney and liver transplant models,156 comparable Jhead. horse antihuman ALG was produced from the serum of horses that had been immunized with leukocytes separated from hu­ The Maturation of Transplantation man lymphoid organs (lymph nodes, spleen, thymus).l55 The first clinical trial of ALG began in 1966. Daily injec­ AI hough it was entirely empirical, the practical framework tions were given to kidney recipients for 1 to 4 postoperative t 'red for the maturation of clinical transplantation was es­ weeks as a short-term adjunct to continuous azathioprine and re4ulallY complete by the end of 1963. Without knowing ei- prednisone.156 After encouraging results were obtained in the sent! . ther the nature of the normal Immune response or the way kidney trial, liver transplantation was resumed, with long sur­ which it had been subverted, It had been learned how to vival of several patients. The successful liver replacements in ;~hablY redirect the immune response with the aid of im­ the summer of 196719 expanded the horizon of transplan­ munosuppression. Surgtcal (see openmg sectIOn) and preser­ tation to the other vital extrarenal organs. Within the suc­ vation techniques (see later) had been developed for trans· ceeding 27 months, heart,20,21 lung,22 and pancreas trans­ :i. plantation of all the organs; these are used cunently with only plantation23 also was accomplished, using variations of the b. minor modifications. Yet, the held of organ transplantatlOn treatment shown in Table 61.4. As had happened with kid­ 1· stalled, and now entered a phase that was euphemistically ney centers in 1963, a wild proliferation of extrarenal (par­ n' tenned "consolidation." The reason was the failure to find ticularly heart) programs followed. However, almost all them improved means of exploiting the principles for control of re­ closed within the next 2 years, because of an overwhelming jection that had been established with azathioprine and pred­ failure rate. nisone (see Table 61.4). Polyclonal ALG was never used in more than about 15% of kidney transplant cases reported to registries up to the early 1980s, in part because it was in no sense a standardized drug Improved Immunosuppression like azathioprine and prednisone. Although the use by Na­ jarian and Simmons I 70 of known numbers of cultured human ANTILYMPHOID STRATEGIES lymphoblasts for accurately timed horse immunization im­ Between 1963 and 1979, the only significant advance in clin­ proved the predictability of the ALG potency, batch·t0-batch

ical immunosuppression was the introduction in 1966 of het­ variations in potency remained problematic. If Antibody ther­ erologous antilymphocyte globulin (ALG),155,156 This step apy" came of age with monoclonal antibodies whose pro­ was a logical extension of Gowan's demonstration of the im­ duction was made feasible by the hybridoma technology of munosuppressive effects of lymphoid depletion with thoracic Kohler and Milstein. l7l OKT3, the first-generation mono­ duct drainage ITDD) in rats142,143 In fact, Woodruff and An­ clonal antibody was directed at all T lymphocytes. 172 Subse­ derson showed that TDD and antilymphocyte serum (ALS) quent antibody preparations, which include less immuno­ had additive effects. 1S7 genic humanized "hybrids," have been directed at discrete roD was clinically used by Franksson and Blomstrand in targets such as T-cell subsets, adhesion molecules, and T-cell 1963 to treat kidney recipients in Stockholm,15S an approach or interleukin 2 receptors. However, when these agents are that resurfaced periodically during the next 2 decades (sum­ used, the "induction" strategy has been essentially the same manzed in [159]). Conditioning with TDD before transplan­ as with the original crude ALG. tatIOn clearly reduced the frequency and vigor of kidney re­ lection, but 30 days of pretreatment were required in CYCLOPHOSPHAMIDE humans, 159,160 compared to the 5 days in Gowan's rats. 142,143 While the experience in this middle era, defined by the first ~wever, the inconvenience, complexity, and expense of triple-drug regimen, demonstrated the feasibility of trans­ o precluded its wide use. 160 For the same reasons, total lymphoid irradiation ITLI)161 which also was an effective planting the vital extrarenal organs, it also indicated that fur­ ther progress would require better baseline immunosuppres­ means of lymphoid depletion but with the disadvantage of sion. Substitution of the alkylating agent, cyclophosphamide, n~t being qUlckly reversible, did not have a lasting impact on for azathioprine was such an effort. 173 The characteristic cycle c InJcal transplantation.162,163 of immunolOgical confrontation and resolution leading to graft In COntrast, ALG was a major turning point for two rea­ acceptance was no different with this drug than with azathio­ :ons. First, it was a critical factor in the emergence of ex- prine-based therapy. However, when the results with kidney frrarenal 0 rgan transpl' antatlon. See on d ,11 . was a prototype d rug and liver transplantation were almost identical to those using i~m which numerous variations evolved. The concept of mit­ azathioprine but at a higher price of complications, the trials b hng cellular Immunity with heterologous antibodies had were discontinued. 174 Although cyclophosphamide thereby be­ c:en proposed by Ilya Metnikoff at the end of the nineteenth ntury164 d . l' d b d b' 165 d 1 came a footnote in the history of organ transplantation, it con­ manIoc, an was revlta lze y In er ltzen - 1 an Wa

100 /~.

80 t ( A 'iii 60 :~ • TAe (n = 1391) , ~ eYA (n = 1835) • 40 ;: • AZA (n = 168) ."• 0." 20 B

a 4 5 0 2 3 Time after transplantation (years)

100 • TAe (n = 1582) ~ eYA (n = 2416) 80 • AZA (n = 190) ~ !..- 'iii 60 > .~

~ 40 iii· a 20 a 2 3 4 5 FIGURE 61.6. Technique of extracorporeal perfUSion with a heart­ 0 lung machine described by MarchioroIl6 Catheters are inserted via Time after transplantation (years) the femoral vessels into the aorta and vena cava as soon as possible fiGURE 61.5. The three eras of orthotopic liver transplantation at after death. The extracorporeal circuit is primed with a glucose or Iheuruversities of Colorado (1963-1980) and Pittsburgh (1981-19931, electrolyte solution to which procaine and heparin are added. The ca­ defined by azathioprine iAZA), cyclosporine ICYAI, and FK 506 daver is thus anticoagulated with the first surge of the pump. Tem­ lucrolirnusl-based iTACI immunosuppression. The same stepwise perature control is provided by the heart exchanger. Cross-clamping improvement was seen with all organs. Top: Patient survival. Bot­ the thoracic aorta limits perfusion to the lower part of the body. IBy tom: Graft survival. These results were about 10% lower than pa­ permission of Experience in Renal Transplantation, W.B. Saunders tient survival in both the cyclosporine (1980-1989) and tacrolimus Co., 1964.215 ) eru11989-1993! because of effective retransplantation, an option that did not exist previously. ORGAN PROCUREMENT Until 1981, transplantation of the extrarenal organs was an complished at first with total body hypothermia of living vol­ unteer kidney donors,213 using methods developed by cardiac unusual event. By late 1981, however, it had become obvious that liver and thoracic organ transplant procedures were go­ surgeons for open-heart operations.2l4 In the experimental A laboratory, Lillehei et al,39 simply immersed the excised in­ ing to be widely used. method of multiple organ procure­ testine in iced saline before its autotransplantation, a method ment was required by which the kidneys, liver, heart, and :lso used by Shumway in developing experimental and clin­ lungs or various combinations of these organs could be re­ moved without jeopardizing any of the individual organs. ICal heart and heart-lung transplantation.4446 Thus, the prin­ "Flexible techniques" were developed2l9,22o which were :le of hypothermia was understood at an early time, al- ough i: was not efficiently applied. quickly adopted worldwide. With the methods, all organs to The hrst major innovation in hypothermia was in the lab­ be transplanted are cooled in situ, rapidly removed in a blood­ less field, and dissected on a back table. The sharing of or­ O?~ry, when canine liver allografts were cooled by infusion gans from a common donor by recipient teams from widely °h C llled fluids into the vascular bed of hepatic allografts via ~ e POrtal vein.42 Before this time, survival of dogs after liver separated centers became routine by the mid-1980s. ansp antation was almost never obtained while afterward Ex VIVO PERFUSION ~cess became routine. In a logical extensi;n to clinical kid­ infu transplantation, the practice was introduced in 1963 of !lex SIng chilled lactated Ringer's or low molecular weight atel~a~ solutlons into renal artery of kidney grafts immedi- Tater then removaPlS vatio oday, intravascular cooling is the first step in the preser- n 1ll0St tot all whole 0. rgan grafts. For cadaver donors, this is o ten do . SCnbed b ne In SitU bY,some variant of the techniq,ue de- COntinu y MarchlOro et al.-l6 lFig. 61.6). ThIS method tor the kidney OUs hypothermic perfUSIOn of cadaveric livers and brain 'ds w~s used clinically long before the acceptance of and Be eat ; Ackerman and SnelF17 and Merkel, Jonasson, rgan"' 8 !lavers W h' populanzed the simpler core cooling of ca aorta. It cold electrolyte solutions infused into the distal 1390 CHAPTER 61 ber components by Belzer et a1. 22-1 resulted in satisfactory kid­ ily of other molecules was delineated with insulin-like h of [ ney preservation for as long as 2 to 3 days. The asanguinous totrophic properties244 Eventually the gene was disc epa_ oVered ,,'It perfusion technique eventually was abandoned in most kid­ that expresses one of these (augmenter of liver reg , tion)245-147 The hepatotrophic factors, most of which enera. plJ( ney transplant centers when it was learned that the quality are cy of 2-day preservation was not better than with the simpler tokines (e.g., hepatocyte growth factors [HGF]J, regulate I' . nW dOl "slush" methods Isee following). Nevertheless, it is expected size, stmcture, regeneration, and metabolic homeostasis lVe{ to : that refinement of perfusion technology will someday permit Studies of hepatotrophic physiology led directly or' d' ln ref tme organ banking. rectly to liver replacement for cure of more than two d 1- hepatic-based inborn errors of metabolism,14.~ inclUdinoz~n titT oth "SLUSH" PRESERVATION milia I hypercholesterolemia.249,25o The role of hepatic t; a­ plantation in first suggestll1g, and then proving, that the . l~ns-IVer we With the so-called static methods, fluids of differing osmotic, governs cholesterol metabolism has been described el oncotic, and electrolyte composition are infused into the cal where238,249-251 Elucidation of the cellular and molecu~e­ allograft beiore placing it in a refrigerated container.22s,226 et: mechanisms was rewarded by bestowal of the 1985 Nob~ tio The solution described by Collins, Bravo-Shugarman, and Prize to Brown and Goldstein Isee Table 61.2) e Terasaki225 (which resembles intracellular electrolyte con­ enl centrations), or modifications of it, were used for almost two ide cal decades. Renal allograft preservation was feasible for 1 to 2 Immunological Screening days, long enough to allow tissue matching and sharing of or­ gans over a wide geographic area. Experiments with hepatic WI 227 The importance of the genetically determined major histo­ allografts by Benichou et al using the Collins-Terasaki so­ In lution and by Wall et ap28 with the plasma-like Schalm so­ compatibility complex IMHC) in determining the immune reo sponse to allografts was evident from investigations by pa: lution led directly to liver sharing between cities, but with a George Snell in inbred mice,252 which in tum derived from et time limitation of only 6 to 8 h. en The introduction for liver transplantation of the Univer­ the work of Peter Gorer (see "the seminal influence of Gorer and Snell"253). However, the information was not clinically ph sity of Wisconsin IUW) solution by Belzer, Jamieson, and applicable. Thus, immunological screening of donors and re­ ca: Kalayoglu,229,23o was the first major development in static idt preservation since the Collins-Terasaki solution,231 The su­ cipients was not done during the volatile developmental pe­ 1 w, periority of the UW solution for preservation of the kidney riod of 1959-1963. The possibility of tissue matching did not begin to emerge until the discovery by Dausset of the first trC and other organs was promptly demonstrated in experimen­ ro, tal models and confirmed in clinical trials232-237 The UW human leukocyte antigen (HLA) in 1958,254 and the discov­ ery in the same year by Van Rood et a1. 255 of antileukocyte preservation doubled or tripled the time of safe preservation th antibodies Isoon shown to be HLA directed) in the sera of Jf the various allografts, making national and international WI pregnant women. ;haring of most organs an economical and practical objective, Lc The report in 1964 by Terasaki256 of the microcytotoxic· iii ity test, with which HLA antigens could be detected sero­ ag rhe Life Sciences logically in minute quantities of sera, was a critical develop­ Ie ment in moving forward with the classification of the Nhile occupying its own unique niche, transplantation has A antigens. re lrawn from and in tum enriched all the other basic and clin­ cal scientific disciplines, Aside from changing the philoso­ af lhy by which organ-defined specialtIes of surgery and medi­ The Crossmatch Principle C{ ine are practiced, transplantation grew parallel with, and As it turned out, the greatest impact of pretransplant tissue g, :ontributed in a major way to, advances in immunology, phar­ matching has been the prevention of hyperacute rejection by e: nacology, oncology (e,g., the role of tumor immune surveil­ observation of ABO compatibility guidelines and the routine d ance I52,238J, infectious disease, intensive care, and anesthe­ use of the cytotoxicity cross match. ri iology. Study of each of the different kinds of allografts has h ielded an organ-specific harvest of special information. Ex­ ABO COMPATIBILITY Cl mples include a better understanding of diabetes mellitus lith pancreas transplantation and of the effects of denerva­ Hyperacute rejection was first observed more than 30 years ,on on cardiopulmonary function with heart and lung trans­ ago when ABO-mismatched renal allografts were transplanted 1 lantation. into patients who had preformed antigraft ABO isoagglu- 1- The liver became the key organ in unmasking the secrets tinins.53,257 After kidneys were lost on the operating table, ar· b f acquired tolerance because of its large content of im­ teriograms of the infarcted organs showed nonfilling of the lUnocompetent leukocytes Isee earlier, and "Allograft Ac­ small vessels, correlating histopathologically with wide­ '" 11 ;ptance versus Acquired Tolerance"). In addition, the func­ spread thrombotic occlusion of the microvasculature. It was r, concluded that high-affinity isoagglutinins in the recipienJ onal complexity of the liver as well as its metabolic n sera had bound to A or B antigens in the graft vessels and lteractions with other abdominal viscera have made hepatic i: ansplantation a "mother lode" for physiological studies,239 parenchymal cells. This finding was consistent wIth rapl In the course of determining the optimal revascularization changes in reCipient isoagglutinin titers that followed organ . auxiliarv 11 vers transplanted to ectopic sites or to the nor­ revascularization. The guidehnes formulated from this expe­ al location,42,2+0,241 it was found that endogenous insulin is rience53 ,25 7 were designed to avoid such antibody confronta­ liver growth iactor,2412-l3 the first such hepatotrophic factor tions Isee Table 6U). , cis be identifled, Using transplantation-denved models, a fam- The ..'iliO rules also apply to heart, liver, and other kin A HISTORY OF CLINICAL TRANSPLANTATION 1391

nsplantation. As was originally observed in 1963 Terasaki's investigations began with a retrospective study aforgan ~~~isrnatched kidneys, however: 53,257 not all organs of the influence of HLA matching on the quality of outcome \\1th All he hostile envIronment of antlgratt Isoagglutmms of patients bearing long-surviving kidney allografts,lls fol­ placed ~n t arne fate. In fact, the longest continuously func­ lowed by a prospective trial in live donor kidney recipients meet t e Sal allograft in the world!06 is a B+ kidney donated treated with azathioprine and prednisone, with or without ad­ ti011tng re~8_year_old A -r male recipient by his younger sis­ junct ALG.279 Consistent with the results in the classic skin !O a then- "ry 31 1963. In addition, it was learned at an early graft investigations in nonimmunosuppressed healthy volun­ 11 JanUa' , . tef 0 hat the liver is more resIstant to antibody attack than teers by Rapaport and Dausset, 280~282 HLA-matched allografts timE t 'os her organs. -, . . .. . had the best survival and function, least dependence on main­ ot h'srocompatiblhty studIes m which human volunteers tenance prednisone, and fewest histopathological abnormali­ In e~sitized with purified A and B blood group antigens, ties in routine 2-year postoperative biopsies.283 Unexpectedly, were. 5 variably increase d'tIters 0 f'lsoagg I" utmms, Rapaport however, a cumulative adverse effect of mismatching in the etcaustng aJ.259 showed accelerate d or h yperacute (h'w Ite gra f)'t re)ec- kidney recipients could not be identified. , f ABO-incompatlble skm grafts transplanted to reClpl- The equally imprecise prognostic discrimination of HLA uon 0 . h ' 1 f with high titers. ThIS result completed t e CITC e 0 ev- matching in cadaver kidney transplant cases also was first entS . f 'b d' h ,.. recognized by Terasaki (with Mickey et aJ.284), and has been Ie.d nee indicating antlgra t antI . 0 les as t e preclpitatlllg cause of hyperacute organ re)ectlOn. evident in analyses up to the present time. With the large sample sizes in United Network for Organ Sharing IUNOS) WITH NON-ABO ANTIBODIES and European databases, virtually every comparison of the dif­ ferent levels of mismatching showed statistical significance. In 1965, hyperacute rejection of a kidney by an ABO-com­ However, the absence of a large or consistent matching effect patible recipient was reported for the first time by Terasaki unless there is a perfect or near perfect match has always been et a].260 Terasaki's observation that the serum of the recipi­ the same. In a recent study of more than 30,000 UNOS pa­ ent of a live donor kidney contained preformed antigraft lym­ tients for whom optimal matches had been sought prospec­ phocytotoxic antIbodies was promptly confirmed in similar tively, approximately 85% of the cases were in the two- to cases by Kissmeyer-Nielsen et a1.261 and others,262,263 The ev­ five-HLA-mismatch spectrum where I-year survival was clus­ idence of a cause-and-effect relationship in the single first case tered within 3%. Subsequent half-life projections thereafter was so clear that Terasaki recommended and immediately in­ were in the narrow spread of 9 to 11 years.28S troduced his now universally applied lymphocytotoxic cross­ Terasaki's conclusions nearly three decades ago breathed match tes t. 260.264 life into the still struggling fields of liver, heart, and lung It has been shown in presensitized animals and humans transplantation. It was a relief to know that the selection of that antibodies, clotting factors, and formed blood elements donors with random tissue matching would not result in an 265 were rapidly cleared by the hyperacutely rejecting grafts. ,266 intolerable penalty. A quarter of a century passed before it Local fibrinolysis from the renal vein also was a consistent could be explained why HLA matching was critical for bone finding, and in exceptional cases, there were systemic co­ marrow, but not organ, transplantation (see next section)_ agulopathies with disseminated intravascular coagulation IDIC)267,268 The findings are comparable to those in the Arthus reaction, inverse anaphylaxis, generalized Shwartzman Allograft Acceptance Versus reaction, and other models of innate immunity.263,267,268 Acquired Tolerance Non-HLA antibodies such as antivascular endothelial cell antibodies also have been associated with hyperacute or ac­ During the Festschrift at Harvard honoring Paul Russell's re­ celerated re)ection.269.27o The vulnerability of extrarenal or­ tirement in late November 1990, Norman Shumway told me gans to this kind of rejection was ultimately demonstrated and Leslie Brent about his text on Thoracic Transplantation experimentally271~273 and clinically. Although the liver was for which he wanted two chapters: one explaining the classic the most antibody resistant,2S8 it too was placed at increased immunological tolerance exemplified by bone marrow trans­ 274 nsk by the presensitized state Hyperacute rejection also plantation, and the other defining the presumably different has been documented in a small number of human organ re­ mechanisms of whole-organ allograft acceptance. On learning CIpients in the absence of detectable antibodies. 263 ,275 that I thought the two were the same in principle, Shumway assigned me to the task of defending this opinion.1H6 TiSsue Matching Evidence was obtained first from investigation of long­ surviving human liver, kidney, and other organ reclpi­ ~stor~callY, it was predicted tissue matching would have to ents,31.32,287-289 and then from detailed confirmatory animal pertected If long-term engrattment of tissues and organs studies290~293 The observation that all 30 patients tested had Was to SUcceed with any degree of reliability and predictabil­ low level (micro-) chimerism conformed perfectly with the Ity, The prophecy was immediately fulfilled with bone mar­ hypothesis being tested that allograft acceptance involved not row transplantation, in which anything less than a perfect or only chimerism, but a bidirectional immune reaction (Fig. near-perfect match between the donor and recipient resulted 61.71. The relative strengths of the opposing immune reac­ ~n CVBD or rejection of the graft.26~19 When similar expec­ tions following organ transplantation were simply the reverse t:tlons Were not met in studies by Paul Terasaki in kidney of those following bone marrow transplantation to the cy­ ansplant recipients the results initially were treated as a toablated recipient (summarized in [33,1061). With this para­ 'U"'" bSClentlfl'C scan da 1 .- n,_" Wh en hIdeater was prove to 1lave digm, it has been possible to view the historical milestones i;en correct, TerasakI emerged as the father of HLA match- of clinical organ as well as bone marrow transplantation in a Ii. _____g and as an endunng symbol of integrity. coherent way.34 1392 CHAPTER 61

importantly, however, it had been advanced in a n --- tive climate in whIch "group think" had already tu~n~cep.· . difterent direction. For the next 30 years, transplantati~n ~l FI munity and tolerance were conceived as products of tIll­ rectional immune reactions ot the kind that could be s:U.di.· in vitro by one-way mixed lymphocyte culture techniq died Immune scribed by Bain and Lowenstein"% and B.ach and Hirschh~~ ~ .• Reaction ~ After chlmensm was dIscovered morgan recipie .. 1992-1993,31-33 it was recognized that the interaction :~s Ul •.O ..•\ ..••.•••• coexisting donor and recipient leukocyte populations Was ~e ~.~,l common factor that underlay both the "acceptance" ind e Time after Transplantation by whole-organ allografts (Fig. 61.8, bottom left) and theUc~ l erance induced with bone marrow (Fig. 61.8, bottom FIGURE 61.7. Contemporaneous host-versus-graft iHVGj and graft­ ri;' versus-host (GVHj reactions in the two-way paradigm of transplan­ This context closed the 30-year intellectual gap between t~~ tation immunology. Following the initial interaction, the mainte­ fields of organ and bone marrow transplantation. Organ.as~ nance of nonreactivity of each leukocyte population to the other is sOClated chlmensm then co~ld be old~~tJhed in a Continuum seen as a predominantly low-grade stimulatory state that may wax of classIc tolerance models o,II,161,~9o-~OO be<>innl'n . h and wane. ' b g Wit the original observations by Owen in freemartin cattle IFig. 61.91. FIG OWl chir Historically, an organ allograft had been envisioned as de­ Organ Engraftment fenseless and vulnerable to immunological attack in propor­ tion to its histoincompatibility IFig. 61.8, top left). The same The immunocompetent donor leukocytes in organ trans. ~rg, dogma in reverse Ii. e., the host was the defenseless target) was plantation are highly immunogenic multilineage "passenger the the conventional view of bone marrow transplantation IFig. leukocytes" of bone marrow origin (including stem and den­ gra 61.8, top right). Only two pioneer workers raised objections dritic cells) that migrate preferentially to host lymphoid or­ act to the definition of transplantation immunology in terms of gans and are replaced in the graft by host cells. The result is a unidirectional immune reaction. In 1960--1961, Simonsen,I34 widespread antigen-specific immune activation of the coex. by and then Michie, Woodruff, and Zeiss,294 postulated that the isting donor and recipient cells, each by the other, which pro­ sur two populations of immune cells in neonatally tolerant mice ceeds in successful cases to variable reciprocal clonal ex· onr managed to coexist in a stable state by becoming mutually haustion and then deletion IFig. 61. 7). an nonreactive while retaining the ability to function collabora­ Engraftment under clinical circumstances requires an um· the tively Ii. e., in a joint immune response to infection). brella of immunosuppression to prevent one cell population ma Although this heretical suggestion resembled the concept from destroying the other, but in some experimental models an< summarized in Figures. 61. 7 through 61.11, the Simonsen­ it occurs spontaneously le.g., after pig liver transplantation reg Woodruff hypothesis was recanted in 1962,295 ostensibly be­ and in many rodent models). The "nullification" of the two thr cause no experimental support could be found for it. More a=s explains the poor prognostic value of HLA matching for 61 do tio One-Way Paradigm (Organ) One-Way Paradigm (Bone Marrow) 1m t lel (J) ~d~. I ~:'" Be Pr to ~;; ~-@ ····::fJi·~:>\X /" :~ trr Defenseless Graft ':,:r .• '...... ' ...... '... !F>-.'... 1...... '.!...... •. , ~ .... \c:,- "'1/,: ~ irr !St 8,u,n!l'~am·8,.nl-M.

Martinez/Good QJ (1) Maintenance (3) (f) ...... clonal Parabiosis Organ Tx c o "",dele1ion ~ (1960) (1992) a. (f) 0) ...', ...... ~ ...... -~ ...... ,.".--...... ---- cr , 0) ...... ;;.. :;.; ...... C :l E E

Leucocyte Depletion (4)

.,";.",,,, i Billingham/Brent Slavin/Strober (1977) Medawar Iidstad/Sachs (1984) Time (1953) Thomas (1987) FIGURE 61.10. The four events that occur in close temporal ap­ FIGURE 61.9. Continuum of chimerism from observations of Ray prOlamation when there is successful organ engraftment. Top. dou­ Owen in freemartin cattle to the discovery m 1992 of rmcTO­ ble acute clonal exhaustion (1, 2) and subsequent maintenance clonal chimerism in organ reCipients. exhaustion [31 plus Ibottomlloss of organ immunogenicity caused by depletion of the graft's passenger leukocytes [41.

organ versus bone marrow t.ransplantation (Table 61.6), and the low incidence of GVH disease (GVHD) followmg the en­ cytes is not possible with conventional doses of cytoabla­ graftment in noncytoablated recipients of immunologically tion,301 the remaining cells will stimulate an alloresponse by active organs, such as the intestine and liver. mature or maturing donor T cells. Nevertheless, under im­ In addition to inducing clonal activation and exhaustion munosuppressive treatment, a weak host-versus-graft reac­ coex· by trafficking to host lymphoid organs, donor leukocytes that tion mounted by these few recipient cells and a parallel graft­ hpro­ survive the initial destructive immune reaction migrate sec­ versus-host reaction mounted by the donor bone marrow cells tI ex· ondarily to nonlymphoid areas, where they do not generate may eventually result in reciprocal tolerance by deletion. an immune response ("immune indifference"). From here These processes represent a mirror image of the events after lum' they may "leak" periodically to the host lymphoid organs and organ transplantation [see Fig. 61.8, bottom right). ation mamtain clonal exhaustion. With clonal exhaustion/deletion Jdels and immune indifference in combination, both of which are ltion regulated by the migration and localization of the antigen,33 Relation to Infectious Disease two the four interrelated events shown schematically in Figure g for 61.10 must occur close together to have organ engraftment: NONCYTOPATHIC MICROORGANISMS double acute clonal exhaustion, maintenance clonal exhaus­ Early workers in transplantation302,303 recognized the resem­ tion, which frequently waxes and wanes, and loss of graft blance of allograft rejection to the response against infections immunogenicity as the organ is depleted of its passenger associated with delayed hypersensitivity, exemplified by tu­ leukocytes. berculosis. With the demonstration of the major histocom­ patibility complex- [MHC-) restricted mechanisms of adap­ Bone Marrow Tolerance tive infectious immunity by Doherty and Zinkemagel in 1973,304-307 it became obvious that allograft rejection must Pretransplant cytoablation renders the recipient susceptible be the physiological equivalent of the response to this kind to immune attack by donor immune cells ii.e., GVHD), con­ of infection. Microorganisms that generate such an adapuve trol of which frequently becomes the principal objective of immune response are generally intracellular and have no or Immunosuppression, rather than the prevention of rejection low cytopathic qualities.308 Isee Table 61.6). Because complete destruction of host leuko- Although MHC-restricted host cytolytic T lymphocytes recognize only infected cells, elimination of all the infected cells could disable or even kill the host. Consequently, mech­ !A:LE 61.6. Differences Between Conventional Bone Marrow ~an Transplantation. anisms have evolved that can temper or terminate the im­ mune response, allowing both host and pathogen to sur­ Bone marrow Organ vive 308,309 These are the same two mechamsms that allow ~------~------~ Recipient cytoablation"..... No survival of allografts (Le., clonal exhaustion/deletion and im­ Critical <- MHC compatibility ~ Not critical mune indifference),33 both of which are governed by antigen GVf.rD migration and localization.33 ,308,309 However, unlike the com­ - Pnncipal complication ~ Rejection Common plex dual immune response of transplantation, infectious 1m­ - Drug-free state ~ Rare TrJlera mumty is essentially a host-versus-pathogen reaction. ~ - Term for success ~ "Acceptance"b \Ote' All ,...... The analogies between transplantation and an mfection "'blish~s . ultterences derive trom this theropeutic step, wh1eb m eUect es- with disseminated noncytopathic microorganisms can be ex­ Cf)unten' d.n unopposed GVH reactlOn in the bone marrow reCIpIent whose :Or' allI~g Imml.lnL: reaCtion is elImlnated. emplified by the common hepatitis vil1.lses, as shown in I1peratlOnal ~I) ierJnce." Figure 61.1133.308.309 The pathogen (antigen I load may rapidly ------~-.~------

-1394 CHAPTER 61

IA»V IR «v V Unopposed (Exhaustion I deletion (Immunologically of immune response) Ignored)

Stable Canibr ., Slate Warts, Papillomas .. in keratinocytes " ..... sadd witt Transplant Acute graft rejection Stable graft Chronic graft rejection Analogue: Leukocyte depletion: (or GVHD) acceptance (or GVHO) ofallogrart ceDt of recipient (cytoablation) all tI TIM E itW' FIGURE 61.11. Variable outcomes after infection with widelv dis­ marrow transplantation. Horizontal axis. time; vertical aXIS . aJ micl ,eminated noncytopathic viruses (or other microorganismsi and load (v. solid line! and host immune response IJR, dashed 1in~IV\! malogies lin the text below the horizontal axes) to organ and bone mon obse to In ncrease during the so-called latent period, but then be dra­ epitope, an epitope that also is found on numerous cytopathic eSlS natlcally and efficiently controlled by antigen-specific effec­ bacteria, protozoa, and viruses. or T cells, which then subside (left panel). The transplant a­ The clinical use of such discordant animal donors will re­ ion analogues are acute irreversible rejection (or intractable quire changing the xenogeneic epitope to one that mimics a Reft ;VHD). Alternatively, a continuously high antigen load with noncytopathic profile, or else elimination of the epitope.310 1. n antigen-specific immunological collapse (second panel) is Although chimpanzees and baboons do not express the Gal :J.uivalent to unqualified acceptance of an allograft. antigen, the clinical xenografts transplanted from these sub­ 2. Between these two extremes, the persistence of both the human primate donors in 196350,51 ultimately were damaged lfectious agent and a strong immune response results in se­ by an uncontrollable innate immune reaction, dominated by aus immunopathology le.g., chronic active hepatitis with a complement activation. Similar innate immune mechanisms 3. ' or C virus infection) comparable to chronic rejection after were recognized in the 19605 to be responsible for the hyper­ ver transplantation (third panel), or, uncommonly, GVHD. acute destruction of ABO·incompatible allografts, or allografts 4. 'Ie conditions in the cytoablated bone marrow recipient transplanted to presensitized recipients Isee earlier,263-268). 5. imic those of an infection by microorganisms (e.g., rabies .d wart viruses) that avoid immune activation by not mi­ Self-Nonself- Discrimination 6. ' ltmg through or to host lymphoid organs lright panel).33 Because immunity and tolerance to alloantigens follow Survival in a hostile environment requires the ability to e same rules as the response to nancytopathic microorgan­ mount a protective immune response while avoiding a reac­ 7.. ns,33 it is not possible with current transplantation prac­ tion of the immune system against self. Transplantation has es to induce tolerance to allografts on the one hand with­ succeeded because it has not lethally eroded this capability, 8. t risking unwanted tolerance to pathogens on the other. In which depends ultimately on the governance of immunolog­ s context, the historical anxiety depicted in Figure 61.4 ical responsiveness or unresponsiveness by migration and 10· 9. s correct. calization of antigen.33 Because the fetus possesses very early T-cell immune function,311-313 the ontogeny of self-nonself· 10. TOPATHIC MlCROORGANISMS discrimination during fetal development can be explained by

the same mechanisms as acquired tolerance in later life, Au' 11. I ~re is no MHC-restricted safety valve for cytopathic mi­ toimmune diseases then reflect unacceptable postnatal per· Jrganisms, which are typically extracellular and generate turbations of the prenatally established localization of self· 12. full resources of the innate as well as the adaptive im­ antigens in nonlymphoid versus lymphoid compartments33 ne system308,309 An uncontrollable innate immune re­ nse involving the effectors shown in Table 61. 7 is pro­ 13 .. ed by discordant xenografts expressing the Gal a Gal Conclusion 14 .. •E 61.7. Effectors Involved in Response to Cytopathic The lesson described in this chapter has been learned many si tes and Discordant Xenografts. 15. times before: all knowledge can be traced to its roots, and ul· first line of defense timately to a seed. For clinical transplantation, the histoncal 'erferons beginning was Medawar's recognition that rejection isan I~· \crophages mune reacnon. Only two pnmary roots sprang trom thiS see . 16. mma/delta T cells turdl killer iNK! cells One was the demonstration by Billingham, Brent, and Meda­ ells war in 1953 that tolerance could be acquired by producing stem 17 pecific or less specific efiectors cell-dnven hematolymphopoietic chimerism5; this concept ul­ mplement timately led to bone marrow transplantation in humans. , l~. Iy interleukins The other root was the demonstration during 1962-1960 tgocytes that kidney allografts could consistently self-induce tolerance A HISTORY OF CLINICAL TRANSPLANTATION 1395

aid of immunosuppression30; all further develop­ 19, Starzl TE, Groth CG, Brettschneider L, et a1. Orthotopic homo­ ,.1tb the [gan transplantation were derivative from this dis­ transplantation of the human liver. Ann Surg 1968;168:392-415. "dlentS, lDT~e assumption reached by concensus in the early 20. Barnard CN. What we have learned about heart transplants. TThorac Cardiovasc Surg 1968;56:457-468. CIlrmthat the twO roots reflected different immune mecha- 21. Dong E as told by Shumway NE and Lower RR. In: Terasaki PI, 6 19 0s 1 d to inadequate explanations of organ allograft ae­ ed. History of Transplantation: Thirty-Five Recollections. Los (I15lD' e and clouded the meaning of successful bone mar- _epwnce , Angeles, Calif: UCLA Tissue Typing Laboratory, 1991:435-449. • , nsplantanon. 22, Derom F, Barbier F, Ringoir 5, et a1. Ten-month survival after "'I' tra ' h' h I b d IV The false assumption, w IC prompt y ecame. ogma, lung homotransplantation in man. J Thorac Cardiovasc Surg dl d succeeding generatIons of SCIentlsts and chmClans 1971 ;61:835-846. sad he context that precluded the synthesis of a clarifying 23. Lillehei RC, Simmons RL, Najarian JS, et a1. Pancreaticoduode­ l\'It ;11 principle of immunology which could be applied to nal allotransplantation: experimental and clinical observations. centra . Ai all transplant, much less nomransplant,. cIrcumstances.. ter Ann Surg 1970;172:405-436. , . discovered in 1992 that organ reClpients had persIstent 24. Goulet 0, Revillon Y, Brousse N, et a1. Successful small bowel It was . 'bl h . I transplantation in an infant. Transplantation (Baltimore I 1992; . ochimerism, It was POSS! e to see t e essentIa com- ira! ~a , 53:940-943 onality of organ and bone marrow transplantatlon, to relate 25. Starzl TE, Rowe M, Todo S, et a1. Transplantation of multiple ~ erYltions after these procedures to the immune response abdominal viscera. 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A HISTORY OF CLINICAL TRANSPLANTATION 1399

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