History of Clinical Transplantation

Hetero (Xeno) Transplantation

The first known attempts at clinical renal transplantation by vascular anastomoses were made between the beginning of the twentieth century and 1923 in France [48], Germany [49], and elsewhere (summarized in [50]) using pig, sheep, goat, and subhuman primate donors. None of the kidneys functioned for long, if at all; and the human recipients died a few hours to 9 days later. No further animal-to-human transplantations were tried again until 1963, after immunosuppression was available [51, 52].

Homo (Allo) Transplantation

In 1936 Voronoy of Kiev, Russia, reported the transplantation of a kidney from a cadaver donor of B⁺ blood type to a recipient of O⁺ blood type [53], in violation of what have become accepted rules of tissue transfer [54, 55] (Table 1). In addition, the allograft was jeopardized by the residual risk of acute mercury poisoning (from a suicide attempt), which had caused the recipient’s renal failure. A final adverse factor was the 6-hour lapse between the donor’s death and organ procurement. The allograft did not produce any urine during the 48 hours of the patient’s posttransplant survival. Although other attempts may have been made by Voronoy [56], another 15 years passed before significant kidney transplant activities were resumed in France.

In 1952 Rene Kuss [57] and Charles Dubost [58] in Paris and Marceau Servelle [59] in Creteil carried out a series of renal transplantations with kidneys removed from convict donors immediately after their execution by guillotine. The next year, the French nephrologist Jean Hamburger, in collaboration with urologist Louis Michon at the Hôpital Necker in Paris, reported a mother-to-son transplantation of a kidney that functioned well for 3 weeks before being rejected [60]. The procedure developed by Kuss and the other French surgeons and used for this first live donor kidney transplantation has been performed hundreds of thousands of times since then. The operation’s relative freedom from chronic morbidity would soon be demonstrated with the identical (monozygotic) twin transplantations of Joseph E. Murray and John Merrill and their associates [61] at the Peter Bent Brigham Hospital in Boston.

The efforts by the French teams were widely known, and visitors flocked to Paris during the early 1950s to learn first-hand from the experience. One of the observers of the extraperitoneal pelvic operation (often called the Kuss procedure in Europe) was John Merrill, as Hume and Merrill et al. [62] described in their account of the first clinical trials at the Peter Bent Brigham Hospital. Among Hume’s nine Boston cases, however, all but one of the allografts were placed in the recipient thigh, revascularized from the femoral vessels, and provided with urinary drainage by skin ureterostomies.

The exceptional case in the Boston series [62] was the first one. The donor and recipient operations were performed in Spring-field, Massachusetts, on March 30, 1951, by L.H. Doolittle. The donor kidney, excised because of a carcinoma of the lower ureter, was implanted in the vacated renal fossa of the recipient after removing the native organ. The recipient patient had been under short-term dialysis care at the Brigham, where the first artificial kidney in the United States had been brought from Holland by Wilhelm Kolff and modified by Harvard engineers, as described in detail by Moore [63].

The next eight operations, in which the allografts were placed in the anterior thigh, were performed by Hume in Boston between April 23, 1951, and December 3, 1952. The report of the nine cases stands as one of the medical classics of the twentieth century, providing an extensive clinical and pathologic profile of renal allograft rejection in untreated human recipients. The descriptions complemented the report of Michon and Hamburger of the live-donor French case (see earlier [60]) and pathfinding studies in dogs by Morten Simonsen in Denmark [38] and of W. James Dempster in England [39]. It is noteworthy that Hume treated some of his patients with adrenal cortical steroids. It was already known from experimental studies that steroid therapy modestly mitigated primary skin graft rejection [64–66] and even slowed the accelerated rejection of presensitized recipients [67].

Although compilation of the Boston series postdated the early French efforts (as generously annotated by Hume), the commitment of the Harvard group to transplantation was evident long before the availability of effective immunosuppression. Hume, who moved in 1956 from Boston to the Medical College of Virginia (Richmond), remained a major force in transplantation until his death in the crash of a private plane (of which he was the pilot) near Los Angeles in May 1973. His friend and colleague, John Merrill, who remained in Boston, drowned off the beach of a Caribbean island in 1984.

None of the European and American efforts to this time, or all together, would have had any lasting impact on medical practice were it not for what lay ahead. The principal ingredients of organ transplantation—immunosuppression, tissue matching, organ procurement (and preservation)—were still unknown or undeveloped. The only unequivocal example of clinically significant allograft function through 1954 was provided by one of the nonimmunosuppressed patients of Hume et al. [62] whose thigh kidney produced life-supporting urine output for 5 months. Similar claims about function of an allograft transplanted to the orthotopic location [68] (i.e., as in Doolittle’s case [62]) or to a non-anatomic site [69] were considered implausible by later critics.

The existence of these cases was public knowledge, but the failure of all the grafts (usually with death of the patient) left little room for optimism. The perception, if not the reality, of hopelessness was changed at the Peter Bent Brigham Hospital 2 days before Christmas 1954 when a kidney was removed from a healthy man by urologist J. Hartwell Harrison and transplanted by Joseph E. Murray to the pelvic location of the donor’s uremic, identical twin brother [61, 70]. Although no effort was made to preserve the isograft, it functioned promptly despite 82 minutes of warm ischemia. The recipient lived for nearly 25 years before dying of atherosclerotic coronary artery disease.

According to Merrill et al. [61], exploitation of genetic identity for whole organ transplantation had been suggested by the recipient’s physician, David C. Miller, of the Public Health Service Hospital, Boston. It already was well known that identical twins did not reject each others’ skin grafts [71]. To ensure identity, reciprocal skin grafting was performed in the Boston twins. Although the identical twin cases attracted worldwide attention, organ transplantation now had reached a dead end. Further progress in the presence of an immunologic barrier would require effective immunosuppression. The possibility of meeting this objective could only be regarded as bleak. To understand why, it is necessary to appreciate not only how barren the landscape of immunology was but also how slowly the preexisting information had been filled in.

A century had passed between the first vaccination procedure in 1796 (Edward Jenner, small pox) and confirmation of the immunization principle by Louis Pasteur (with chicken cholera and rabies). The proof obtained by Robert Koch that microorganisms caused anthrax (1876) and subsequently many other infectious diseases stimulated a search for the host’s protective mechanisms. This search yielded components of the immune response: antibodies [Emil Adolf Von Behring and Shibasaburo Kitasato (1890)], immune cells [Ilya Metchnikoff (1884)], and complement [Jules Bordet (1895)]. In addition, Paul Erlich developed the side chain theory (1890), according to which each cell has a vital center of protein substance and a series of side chains (later known as receptors) to which toxic substances and nutrients were absorbed and then assimilated. In 1910 Erlich introduced the first antimicrobial drug, an arsenical compound effective against syphilis, yaws, and several other infections.

Decades passed between the cluster of great contributions at the turn of the twentieth century and the proposal by F. McFar-lane Burnet that antibodies were produced in each individual only to those antigens to which he or she was exposed [14]. The lack of major movement between events is evident from a list of Nobel Prizes [72] (Table 2). Although 6 of the first 17 Nobel laureates (1901–1919) were honored for work relevant to immunology/transplantation, there was only one more example (Karl Landsteiner, ABO blood groups) among the next 57 (1920–1959). Beginning with Burnet and Medawar (see above), 17 of the 77 laureates since 1960 have been directly responsible for, contributed to, or directly benefited from, advances in transplantation (Table 2).

In Burnet’s original hypothesis of immunity, antibody synthesis was postulated to occur after an antigen locked onto a membrane-bound receptor (a version of the antibody) displayed at the surface of an immune cell. After binding the antibody, the cell proliferated, producing a clone that secreted identical antibodies (the clonal selection theory). Nossal subsequently proved that the clone rose from a single cell (“one cell/one antibody”) [75]. Although Burnet’s hypothesis was not yet complete, it was to become the cornerstone of modern immunology.

With Recipient Cytoablation

The transition of tissue and organ transplantation from an exercise in futility to tenuous practicality involved a surprisingly small number of advances, which were interspersed over long periods of frustration. After Medawar’s demonstration in 1944 that rejection was an immunologic event [3, 4], a logical and inevitable question was: Why not protect the organ allograft by weakening the immune system? This idea was tested in rabbits during 1950–1951 with cortisone [64, 65] and total body irradiation [76]. Both techniques prolonged skin graft survival for only a few days.

Neither these results, nor those reported with cortisone in 1952 by Cannon and Longmire [66] in a chicken skin graft model generated much optimism. However, the Cannon–Longmire report contained three observations that, in retrospect, presaged not only the acquired neonatal tolerance produced by Billingham, Brent, and Medawar the following year but also the most important clinical advances in transplantation of the succeeding decades. First, skin grafts exchanged between 1-day-old chicks of different breeds had a high rate of initial engraftment and a 6% incidence of permanent take. Second, the window of neonatal opportunity was gone by 4 days. Third, and most important, the percent of permanent engraftment of neonatally transplanted skin was increased to more than 20% by a course of cortisone, with no increase of mortality.

The significance of the third observation was recognized by Cannon and Longmire who wrote: “Although the cortisone did not entirely prevent a reaction in the homograft, it did decrease the incidence of reaction. Even more important, the increased incidence of reaction [sic] free grafts appeared to maintain itself after the drug was discontinued. This phenomenon is one which up to the present time has not been found in homograft experiments on mammals and humans.”

Despite a confirmatory follow-up study in 1957 [77], the neglected Cannon–Longmire article faded quickly from the collective memory of both basic scientists and clinicians. In contrast, the achievement of acquired neonatal tolerance by Billingham et al. in 1953 [5, 9] ignited interest in transplantation as never before. Two years later, Main and Prehn [78] attempted to simulate in adult mice the environment that allowed the acquisition of neonatal tolerance. The three steps were (1) to cripple the immune system with supralethal total body irradiation (TBI); (2) to replace it with allogeneic bone marrow (producing a hematolymphopoietic chimera); and (3) to engraft skin from the same inbred strain as the donor of the bone marrow.

The experiments were successful [79, 80]; but as with the neonatal tolerance model, lethal GVHD could be avoided only when there were “weak” histocompatibility barriers. Applying the chimerism strategy for kidney transplantation in beagle dogs in Cooperstown, New York, Mannick et al. [80] reported good renal allograft function in a supralethally irradiated recipient, which also was given donor bone marrow and was a hematolymphopoietic chimera; the animal lived for 73 days before dying of pneumonia. Because it was demonstrated later that this outcome depended on the identity of the dog lymphocyte antigens (DLA) [81, 82], an accidental DLA match was suspected in retrospect to have been present in Mannick’s experiment. Efforts by Hume et al. [83] and subsequently by Rapaport et al. [84] and others to broaden the range of acceptable histocompatibility inevitably led to lethal GVHD, rejection, or both.

With Drug Immunosuppression

After it was learned that TBI alone could result in prolongation of kidney allografts, it was logical to focus the search for immuno-suppressive drugs on myelotoxic agents whose effects mimicked those of irradiation. In September 1960 Willard Goodwin of Los Angeles produced severe bone marrow depression with metho-trexate and cyclophosphamide in a young female recipient of her mother’s kidney. The patient subsequently developed multiple rejections that were associated with bone marrow recovery. They were temporarily reversed with prednisone several times during the 143 days of survival. It was the first example of protracted human kidney allograft function with drug treatment alone [93]. However, the case was not reported until 1963.

Kidney transplant surgeons were quick to realize that bone marrow depression should be avoided, not deliberately imposed, following the demonstration by Schwartz and Dameschek [94] that 6-MP in a nontransplant rabbit model was immunosuppressive in submyelotoxic doses. Within a few months after their seminal discovery, Schwartz and Dameschek [95] and Meeker [96] (working with Condie, Weiner, Varco, and Good) showed that 6-MP caused a dose-related delay of skin graft rejection in rabbits. Aware of these results but independent of each other, Calne [97] in London and Zukoski, Lee, and Hume [98] in Richmond, Virginia, demonstrated the same thing in the canine kidney transplant model. In June 1960 Calne moved from the Royal Free Hospital to join Murray at the Peter Bent Brigham Hospital (Boston) for further preclinical studies of 6-MP and its analogue azathioprine [87, 99–101].

The two drugs had been developed originally by Gertrude Elion and George Hitchings as antileukemia agents [102]. Their possible use for transplantation was greeted at first with feverish enthusiasm because it was generally conceded that recipient cytoablation would permit success in only occasional cases of human renal transplantation. Although approximately 95% of the mongrel canine kidney recipients treated with 6-MP or azathioprine died within less than 100 days from rejection or infection, occasional examples were recorded of long-term or seemingly permanent allograft acceptance [103–106] following discontinuance of a 4- to 12-month course of immunosuppression. The number of these animals was discouragingly small, but it was an accomplishment never remotely approached using TBI, with or without adjunct bone marrow. Survival of Mannick’s single cytoablated animal for 73 days after combined bone marrow and kidney transplantation had been the previous high water mark in dogs (see earlier [80]).

The survival of some of Calne’s animals beyond 6 months led to the decision at the Brigham to begin clinical trials with chemical immunosuppression. However, the poor therapeutic margin of the 6-MP and azathioprine when used alone in dogs was recognized. Calne and Murray also were forewarned by an earlier clinical experience of Hopewell, Calne, and Beswick [107], which was not published until 1964, in which 6-MP had been used to treat three kidney recipients (including one with a living donor) during 1959–1960; all three recipients had died.

Consequently, the canine studies of 6-MP and azathioprine in Boston were highly focused on finding more effective drug combinations [87, 99, 101, 108]. Although adrenal cortical steroids were tested, they did not appear to potentiate the value of azathioprine [99, 101], prompting Murray in his clinical trial to opt for adjunct cytotoxic agents such as azaserine and actinomycin C [87]. Only one of the first 10 kidney recipients treated with either 6-MP (n = 2) or azathioprine-based immunosuppression (n = 8) survived more than 6 months (the last one in Table 3) [87, 111].

At the nadir of the resulting pessimism, two reproducible observations, first in dogs and then in humans, were made at the University of Colorado. Taken together, these findings profoundly shaped future developments in transplantation of all organs and eventually of bone marrow. The observations were encapsulated in the title of a report published in October 1963: “The Reversal of Rejection in Human Renal Homografts with the Subsequent Development of Homograft Tolerance” [31].

The reversal was readily accomplished by temporarily adding unprecedented high doses of prednisone (200 mg/day) to baseline immunosuppression with azathioprine. The evidence that the living donor kidneys had self-induced tolerance under an umbrella of immunosuppression was equally clear. Most of the recipients had a subsequent progressively diminishing need for immunosuppression, usually to doses lower than those that initially failed to prevent rejection. The tolerance was complete enough to allow the patients to go home to an unrestricted environment. Nine of the first ten of these kidney recipients achieved prolonged graft survival [31], including two who bear the longest continuously functioning allografts in the world today (more than 35.5 years) and have been free from immunosuppression for 32 and 4 years, respectively [109].

The practical and theoretic implications of these observations were recognized throughout the report [31]:

A state of relative immunologic non-reactivity seems to have been produced which has lasted for as long as 6 months. … It is not known whether this is due to a change in the antigenic properties of the homograft, or to an alteration in the specific [host] response to the stimulus of the grafted tissues. The apparent host–graft adaptation does, however, provide some hope for prolonged functional survival… . It would seem probable that the [therapeutic] principles, as defined with the kidney, can eventually be applied to other organ homografts… . The prior knowledge that a rejection crisis is almost a certainty and that it usually can be managed by relatively conservative means should serve as a deterrent to the excessive use of measures that may cause fatal bone marrow depression… . It is also conceivable that the avoidance of a primary host–graft reaction by these means [excessive immunosuppression] would prevent the adaptive process.

At the time this bellwether series was compiled between the autumn of 1962 and April 1963, the only other active clinical transplantation programs in the United States were in Richmond (directed by David Hume) [110] and at the Peter Bent Brigham Hospital in Boston (directed by Joseph Murray and John Merrill) [111]. The important earlier program of Willard Goodwin at UCLA (see earlier [93]) had been closed because all of the recipients died in less than 5 months. In Europe, TBI briefly remained the preferred treatment at the long-standing Paris centers of Jean Hamburger and Rene Kuss, whereas Michael Woodruff of Edinburgh had begun testing azathioprine [112].

The results in the Colorado series, and more importantly an exact description of the strategy that had been used to induce variable degrees of incomplete tolerance (Table 4), created a surge of new activity. Within 12 months new kidney transplant centers proliferated in North America and Europe. Most of these second-generation programs remain in operation today.

The observations in the original kidney recipients were promptly confirmed. However, the proposed explanation for these successes (i.e., graft alteration plus loss of specific immunologic responsiveness [31]) was controversial and remained so for the next three decades (see Allograft Acceptance versus Acquired Tolerance, below). Except for reports from the University of Colorado, the term “tolerance” was studiously avoided from 1964 onward when referring to the long-surviving dogs and human kidney recipients produced by the end of 1963.

The article most often quoted as contravening tolerance was that of Murray et al. [106] despite the fact that, as the authors took pains to make clear, the evidence in their report was inconclusive and involved only two canine experiments of a potentially crucial nature. The two long-surviving dogs had been given renal homografts 9 and 18 months previously and had been treated for most of these times with one of the purine analogues. Renal function was deteriorating at the time contralateral kidneys from the original donors were transplanted. The second organs were rejected after 23 and 3 days, respectively, as would be expected.

In commending Murray’s 1964 report and conclusions, Medawar wrote [116]¹:

There is, however, something special about renal homografts, as [Michael] Woodruff’s appraisal in this volume makes very clear. A synoptic survey of more than 1000 renal homografts in dogs carried out by Murray and his colleagues [Murray, Ross Shiel, Moseley, Knight, McGavic & Dammin, 1964] [106] has shown that foreign kidneys do sometimes become acceptable to their hosts for a reason other than acquired tolerance in the technical sense. … There has been an adaptation of some kind—a possibility Woodruff has long urged us not to overlook [117, 118] though there is no reason to believe it an antigenic adaptation.

One possible explanation is the progressive and perhaps very extensive replacement of the vascular endothelium of the graft by endothelium of host origin, a process that might occur insidiously and imperceptibly during a homograft reaction weakened by immunosuppressive drugs.… Another possibility, raised by R.Y. Calne [though not mentioned by him in his contribution to this volume] is the laying down of a protective coat of host antibody on the endothelial inner surface of the graft—an explanation which would classify the phenomenon under the general heading of “enhancement.”

These disclaimers notwithstanding, the commonality of the rejection barrier for different organs was self-evident, as was the likelihood that the means of inducing acceptance of one organ could be used for all the others [119]. There also was evidence from earlier experiments that a liver allograft could protect other donor tissues and organs. It had been noted in 1962 that intestine and pancreas had little histopathologic evidence of rejection in untreated canine recipients if they were components of multivisceral allografts that also included the liver [120]. These observations were confirmed 30 years later in a rat version of the same multivisceral procedures [121, 122].

Most convincingly at an experimental level, it was shown in 1964 that orthotopic canine liver allografts could induce and maintain their own acceptance far more frequently and permanently than renal allografts, even with a treatment course of azathioprine as short as 4 months [123, 124]. Soon thereafter, spontaneous engraftment was demonstrated after liver transplantation in untreated outbred pigs [125–129], many of which passed through self-resolving rejection crises [128, 130, 131].

Thus it already was clear by 1964–1965 that the liver is the most tolerogenic organ. During the late 1960s and early 1970s, Calne, Zimmerman, and Kamada formally proved that the liver tolerization extended to other donor tissues transplanted at the same time or later, first in untreated outbred pigs [132] and then without immunosuppression in selected rat strain combinations [133–135]. Although they were important, the experimental studies with hepatic allografts only affirmed the conclusion reached with the 1962–1963 experience in clinical renal transplantation suggesting that all organs were capable of inducing tolerance. As with liver allografts, the self-induction of donor-specific tolerance by heart and kidney allografts without the aid of immunosuppression was later demonstrated by Corry et al. [136] and Russell et al. [137] in selected mouse strain combinations.

The key mechanism of kidney-induced allograft acceptance was suggested as early as 1964 to be clonal exhaustion [138]. This concept was developed more fully for liver allografts in Figure 2, published in 1969 [139]. Induction of the activated clone by alloantigen was depicted via host macrophages rather than by antigen-presenting dendritic cells, which would not be described until 1973 [140]. In the text accompanying the figure, it was pointed out that exhaustion and deletion of an antigen-specific clone had been postulated by Schwartz and Dameschek as early as 1959 to be the mechanism of the tolerance to heterologous protein induced in rabbits with the aid of 6-MP [94]. In addition, Simonsen had suggested in 1960 that clonal exhaustion induced by allogeneic splenocytes could lead to the acquisition of tolerance in adult animals in the absence of immunosuppression [141].

The error of making a semantic distinction between tolerance and graft acceptance was understandable. The picture that had emerged from the remarkable accomplishments with clinical kidney transplantation between January 1959 and the spring of 1963 was not a product of new insight in immunology. Instead, successful organ transplantation was an intellectually troubling and inexplicable violation of the immunologic rules of the time. The revolution in immunology that had already begun and would continue for the next third of a century did little to change this view.

The Burnet antibody hypothesis of clonal selection (see earlier [14]) was validated and extended to cellular immunity by the late 1950s [142–144], but it had minimal influence on the clinical development of transplantation. Neither did many other key advances in immunology which were either contemporaneous with, or came after, the rise of organ transplantation. The role of the thymus in the ontology of the immune system and in the postnatal immune function of rodents was discovered in 1961 (by Jacques Miller [145, 146]). However, thymectomy in humans did not significantly alter either the early or late course of kidney transplant recipients [147, 148]. Lymphocytes were not formally assigned a function until 1963 (by James Gowans [149, 150]), although workers in transplantation were aware several years earlier that these mononuclear leukocytes were the cellular agents of allograft rejection [13, 151, 152] (Fig. 3). By the time the distinction was clearly established between T and B lymphocytes, transplantation was an established specialty of clinical medicine.

Thus the ascension of organ transplantation came as a surprise to most immunologists. Even as the clinical advances had begun to unfold, Burnet [144] had written in the New England Journal of Medicine that “much thought has been given to ways by which tissues or organs not genetically and antigenically identical with the patient might be made to survive and function in the alien environment. On the whole, the present outlook is highly unfavorable to success.” Pessimism also was deeply ingrained in conventional practitioners of medicine. Well into the 1960s editorials were published in major clinical journals questioning both the inherent feasibility and the ethnical basis of transplantation procedures [153]. As a consequence, transplantation acquired a renegade image, a burden soon compounded by difficulties in extending its reach to the replacement of vital organs other than the kidney.

One dilemma, as it was perceived at the time, is shown in Figure 4 [154]. It was feared that chronic drug immunosuppression powerful enough to prevent organ allograft rejection would render the recipient hopelessly vulnerable to indigenous and environmental pathogens. Early reports of infectious disease complications in the early Colorado recipients [155] and elsewhere gave warning that dire consequences might, in time, be in store for all recipients. It also was suspected that immune surveillance to tumors would be eroded, a possibility that was verified but shown to be manageable by 1968 [156–158].

Autopsy studies in failed clinical cases revealed a typical pattern. Infections for which specific antibiotics were available could be largely controlled. However, opportunistic microorganisms of normally low pathogenicity were overrepresented and appeared at autopsy to be the main cause of death [159]. Of these infections, cytomegalovirus (CMV) was the most common and most lethal. The presence of Pneumocystic carinii as a co-infection with CMV [160] premonitored the lethal role of this combination of infectious agents in the AIDS epidemic in the nontransplant population that lay two decades ahead.

Improved Immunosuppression

Organ Procurement and Preservation

The sudden arrival of clinical kidney transplantation during 1962–1963 was so unexpected that little collateral research or other formal preparation had been made to preserve organs. Although kidneys were successfully transplanted in the pioneer identical twin cases despite protracted periods of warm ischemia, the maturation of clinical transplantation could not proceed without effective organ conservation. This was accomplished at first with total body hypothermia of living volunteer kidney donors [217] using methods developed by cardiac surgeons for open heart operations [218]. In the experimental laboratory, Lillehei et al. [40] simply immersed the excised intestine in iced saline before its autotransplantation, a method also used by Shumway when developing experimental and clinical heart and heart-lung transplantation [45–47]. Thus the principle of hypothermia was understood at an early time, although not efficiently applied.

The first major innovation in hypothermia was in the laboratory, when canine liver allografts were cooled by infusion of chilled fluids into the vascular bed of hepatic allografts via the portal vein [43]. Before this time, dogs after liver transplantation was almost never survived, whereas afterward success became routine. In a logical extension to clinical kidney transplantation, the practice was introduced in 1963 of infusing chilled lactated Ringer’s or low-molecular-weight dextran solutions into the renal artery of kidney grafts immediately after their removal [219].

Today, intravascular cooling is the first step in the preservation of all whole-organ grafts. For cadaver donors, this is most often done in situ by some variant of the technique described by Marchioro et al. [220] (Fig. 6). This method for the continuous hypothermic perfusion of cadaveric livers and kidneys was used clinically long before the acceptance of brain death. Ackerman and Snell [221] and Merkel, Jonasson, and Bergan [222] popularized the simpler core cooling of cadavers with cold electrolyte solutions infused into the distal aorta.

Crossmatch Principle

As it turned out, the greatest impact of pretransplant tissue matching has been the prevention of hyperacute rejection by observing ABO compatibility guidelines and routine use of the cytotoxicity crossmatch.

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 transplantation, in which anything less than a perfect or near-perfect match between the donor and recipient resulted in GVHD or rejection 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 father of HLA matching and as an enduring symbol of integrity.

Terasaki’s investigations began with a retrospective study of the influence of HLA matching on the quality of outcome of patients with long-surviving kidney allografts [280], followed by a prospective trial in live donor kidney recipients treated with azathioprine and prednisone, with or without adjunct ALG [281]. Consistent with the results in the classic skin graft investigations in nonimmunosuppressed healthy volunteers by Rapaport and Dausset [282–284], HLA-matched allografts had the best survival and function, the least dependence on maintenance prednisone, and the fewest histopathologic abnormalities in routine 2-year postoperative biopsy specimens [285]. Unexpectedly, however, no cumulative adverse effect of mismatching in the kidney recipients could be identified.

The equally imprecise prognostic discrimination of HLA matching in cadaver kidney transplant cases also was first recognized by Terasaki (with Mickey et al. [286]) and has been evident in analyses up to the present time. With the large sample sizes in United Network for Organ Sharing (UNOS) and European databases, virtually every comparison of the different levels of mismatching showed statistical significance. However, the absence of a large or consistent matching effect unless there is a perfect or near-perfect match has always been the same. In a recent study of more than 30,000 UNOS patients for whom optimal matches had been sought prospectively, approximately 85% of the cases were in the two- to five-HLA mismatch spectrum, where 1-year survival was clustered within 3%. Subsequent half-life projections thereafter were in the narrow spread of 9 to 11 years [287].

Terasaki’s conclusions nearly three decades ago breathed life into the still struggling field of liver, heart, and lung transplantation. It was a relief to know that the selection of donors with random tissue matching would not result in an intolerable penalty. A quarter of a century passed before it could be explained why HLA matching was critical for bone marrow, but not organ, transplantation (see the section that follows).

Organ Engraftment

The immunocompetent donor leukocytes in organ transplantation are highly immunogenic, multilineage “passenger leukocytes” of bone marrow origin (including stem and dendritic cells) that migrate preferentially to host lymphoid organs and are replaced in the graft by host cells. The result is widespread antigen-specific immune activation of the coexisting donor and recipient cells, each by the other, which proceeds in successful cases to variable reciprocal clonal exhaustion and then deletion (Fig. 7).

Engraftment under clinical circumstances requires an umbrella of immunosuppression to prevent one cell population from destroying the other; but in some experimental models it occurs spontaneously (e.g., after pig liver transplantation and in many rodent models). The “nullification” of the two arms explains the poor prognostic value of HLA matching for organ versus bone marrow transplantation (Table 6) and the low incidence of GVHD following the engraftment in noncytoablated recipients of immunologically active organs, such as the intestine and liver.

In addition to inducing clonal activation and exhaustion by trafficking to host lymphoid organs, donor leukocytes that survive the initial destructive immune reaction migrate secondarily to nonlymphoid areas, where they do not generate an immune response (“immune indifference”). From here they may “leak” periodically to the host lymphoid organs and maintain clonal exhaustion. With clonal exhaustion/deletion and immune indifference in combination, both of which are regulated by the migration and localization of the antigen [34], the four interrelated events shown in Figure 10 must occur close together to have organ engraftment: double acute clonal exhaustion, maintenance clonal exhaustion (which frequently waxes and wanes), and loss of graft immunogenicity as the organ is depleted of its passenger leukocytes.

Bone Marrow Tolerance

Pretransplant cytoablation renders the recipient susceptible to immune attack by donor immune cells (i.e., GVHD), control of which frequently becomes the principal objective of immunosuppression, rather than the prevention of rejection (Table 6). Because complete destruction of host leukocytes is not possible with conventional doses of cytoablation [303], the remaining cells stimulate an alloresponse by mature or maturing donor T cells. Nevertheless, under immunosuppressive treatment, a weak host-versus-graft reaction mounted by these few recipient cells and a parallel graft-versus-host reaction mounted by the donor bone marrow cells may eventually result in reciprocal tolerance by deletion. These processes represent a mirror image of the events after organ transplantation (Fig. 8, bottom right).

Relation to Infectious Disease

Self/Non-self Discrimination

Survival in a hostile environment requires the ability to mount a protective immune response while avoiding a reaction of the immune system against self. Transplantation has succeeded because it has not lethally eroded this capability, which depends ultimately on the governance of immunologic responsiveness or unresponsiveness by migration and localization of antigen [34]. Because the fetus possesses early T cell immune function [313–315] the ontogeny of self/non-self discrimination during fetal development can be explained by the same mechanisms as acquired tolerance during later life. Autoimmune diseases then reflect unacceptable postnatal perturbations of the prenatally established localization of self antigens in nonlymphoid versus lymphoid compartments [34].

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