Anthony Cerami Award in Translational Medicine

A Journey in Science: The Birth of Organ Transplantation with Particular Reference to Alloengraftment Mechanisms

Thomas E Starzl

University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America

Online address: http://www.molmed.org doi: 10.2119/molmed.2014.00254

I was born and raised in LeMars, Iowa dition with repetitive low-voltage ven- debate for nearly 80 years, largely be- (population 5,000). After graduating tricular stimulation (7). After this demon- cause of the confusing literature gener- from high school and serving in the stration of its efficacy, cardiac pacemak- ated by experimental and clinical studies Navy (1944–1945), I earned a BA degree ing was promptly applied clinically. of portacaval shunt. In 1955, the question from Westminster College (Missouri) and These early research experiences, first resurfaced in the context of the canine MD and PhD degrees from Northwest- in neuroscience and then in cardiac auxiliary liver transplant model de- ern University (1947–1952). My PhD the- physiology, epitomized the two ends of scribed by C Stuart Welch at Albany sis in neurophysiology under the precep- the spectrum within which I labored all Medical College (8). torship of Horace W Magoun consisted the rest of my professional life: a search With Welch’s operation, the double of four interrelated articles (1–4) that col- at one extreme for fundamental biologic blood supply of the native liver was left lectively continue to gather 5–10 citations mechanisms and at the other for practi- intact, whereas an extra liver (an allo- per year after nearly 65 years (Web of cal remedies with which to treat human graft) was rearterialized and provided Science, Thomson Reuters, Philadelphia, diseases. After I returned to surgical res- with a high volume of portal venous in- PA, USA). ident duties (1954–1959), a stage large flow from an alternative source. The After completing a 1-year surgical in- enough to accommodate both kinds of “substitute” portal blood consisted of in- ternship at Johns Hopkins Hospital in activity emerged from my new interest ferior vena caval venous return from the June 1953, I suspended clinical training in the liver, its double blood supply dog’s lower body and hind legs (Figure 1, for 18 months to do an experimental and ultimately its transplantation left). When the transplanted hepatic allo- study of complete heart block, a compli- (www.starzl.pitt.edu). grafts shrank to almost half the size cation encountered with some of the first The specific issue at first was whether within a few days, the acute atrophy was human open heart operations. After per- portal venous blood had qualities that attributed to rejection. fecting a model of heart block in dogs were important for optimal liver function Based on off-duty studies of portacaval and elucidating its pathophysiology (5,6), and overall metabolic homeostasis. This shunt in dogs, my alternative interpreta- I invented a safe method to treat the con- question had been a subject of periodic tion was that Welch’s auxiliary allografts had been deprived of liver-supporting (hepatotrophic) factors in the portal blood, to which the native liver had pri- Address correspondence to Thomas E Starzl, University of Pittsburgh School of Medicine, mary access and high avidity. To test the 200 Lothrop St., Pittsburgh, PA 15213-2582. Phone: 412-383-1346; Fax: 412-624-2010; E-mail: hypothesis, I developed two more proce- [email protected]. dures during 1958–1959: simple liver re- Submitted December 16, 2014; Accepted for publication December 16, 2014; Published placement (Figure 1, middle) (9,10) and Online (www.molmed.org) June 25, 2015. replacement of the liver plus all of the other intraabdominal organs (Figure 1, right) (11). The three models in combination fueled two avenues of research.

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deficiencies. In a second model that pre- saged clinical bone marrow transplantation for many other indications, Main and Prehn (17) obtained similar tolerance in adult mice by enfeebling their immune reactivity with irradiation before transplant- ing them with donor bone marrow cells. Such experiments were feasible only when there was a close match of mouse donor and recipient tissue (histocompati- bility) antigens. Without such a match, the immune competent donor cells were either rejected or caused graft versus host disease. Another 15 years would pass before enough human leukocyte antigens were identified to permit the prerequisite matching. Consequently, clinical bone marrow transplantation was not accomplished Figure 1. Three kinds of liver transplantation developed between 1955 and 1958 in dogs. until 1968. In contrast, kidney allografts Left: Welch’s auxiliary liver transplantation. Middle: Complete liver replacement. Right: were transplanted with 1 year or longer Multivisceral transplantation. The allograft organs are colored blue. Illustration by Jon Coulter, M.A., C.M.I. survival without tissue matching, leukocyte infusion or evidence of chimerism in eight human recipients during the The first investigative pathway con- Animals permanently endowed with 1959–1962 period (Table 1) in which I cerned the metabolic cross-regulation of donor cells (donor leukocyte chimerism) was developing the canine liver trans- the different abdominal organs. By dem- could accept other tissues from the same plant models. onstrating that primary hepatic access to donor but from no other donor (donor- Patients 1–7 had been sublethally irra- endogenous insulin and other molecules specific tolerance). This “neonatal toler- diated in advance of transplantation with in portal blood played a crucial role in ance” model was the experimental virtually no immunosuppression after- the control of liver size, ultrastructure, surrogate of human bone marrow trans- ward. The nonirradiated eighth recipient function and the capacity for regenera- plantation for the treatment of immune was treated daily after transplantation tion (12,13), the “hepatotrophic” research contributed importantly to the scientific base of liver transplantation while foster- Table 1. Characteristics of the first successful transplantations of kidney allografts with ≥ ing fundamental nontransplant research 6 months’ survival. that continues to the present day in re- Donor generative medicine (14) and intermedi- Physician Site Date relationship Survival ary metabolism (15). Joseph E Murray Boston, MA 24 January 1959 Fraternal twin 20 years The second developmental pathway Jean Hamburgera Paris, France 22 June 1960 Fraternal twin 26 years involved the potential use of liver, kid- Rene Küssa Paris, France 22 June1960 Unrelated 18 monthsb ney and other kinds of organ transplan- Jean Hamburgera Paris, France 19 December 1960 Mother 22 monthsb tation for the treatment of human dis- Rene Küssa Paris, France 12 March 1961 Unrelated 18 monthsb eases. Although the initial prospects Ralph Shackman London, England 16 March 1961 Brother 3 years seemed bleak, this became the dominant Jean Hamburgera Paris, France 12 February 1962 Cousin 15 yearsc d objective by the end of 1958. The only ev- Joseph E Murray Boston, MA April 1962 Unrelated 17 months idence that tissue or organ rejection Thomas E Starzl Denver, CO 1961–1963 Mixed series >50 years might be avoidable had come from ex- For annotations, see Starzl and Fung (44). periments reported 5 years earlier by aKuss and Hamburger described periodic administration of adrenal cortical steroids with Billingham, Brent and Medawar showing these patients. that allogeneic spleen cells could be bPatient death occurred at listed time. transplanted into immunologically im- cPatient underwent successful retransplantation in the 1970s. mature mice (16). dFirst success with drugs-only immunosuppression (no radiation).

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with azathioprine, a drug for which pre- versal of rejection in human renal homo- ponent of the canine liver operation. clinical testing was done in dogs by Roy grafts with subsequent development of After single failed attempts in Boston (at Calne (with Joseph Murray in Boston, homograft tolerance” (18). “the Brigham”) and in Paris, all human MA) and Charles Zukoski (with David Although none of the kidney recipi- liver transplant activity ceased world- Hume in Richmond, VA). Although the ents were off immunosuppression at the wide until the summer of 1967. possibility of pharmacologic immuno- time of the reports, tolerance was in- During the nearly 4-year moratorium, suppression had been greeted with opti- ferred from a declining need for treat- problems that contributed to the 1963 mism, this collapsed when, in a clinical ment after rejections were reversed. In failures were systematically addressed: renal transplant trial of azathioprine at some cases, the need eventually de- blood coagulation, organ preservation, the Peter Bent Brigham Hospital (Bos- clined to zero, exemplified by five pa- infection, complications of veno-venous ton), the only survival exceeding 6 tients in the original Colorado series bypasses and immunosuppression. In months in more than a dozen cases was who currently bear the world’s longest addition, organ graft availability was that of the eighth patient in Table 1. surviving kidney allografts after 50–52 revolutionized by acceptance of brain By this time, I had moved to the Uni- posttransplant years. All have been off death. After reopening the hepatic trans- versity of Colorado (Denver) and ob- immunosuppression for 14–50 years plant program in July 1967, multiple ex- tained a supply of azathioprine for its (19). amples of liver recipient survival for evaluation in our canine kidney and liver At the time the iconic Denver clinical more than 1 year were produced (23). In transplant models. In conformity with series was inaugurated in 1962, the only the autumn of 1969, I published a second studies done elsewhere, only 5–10% of other kidney transplant program in book, this one entitled Experience in He- the dogs survived for 100 d. When daily America with clinical activity was at the patic Transplantation (24). treatment was then stopped in a step not Peter Bent Brigham Hospital in Boston. During the next dozen years, I contin- taken by other investigators, some of the Guided by the freely shared information ued to do a small number of liver trans- canine liver and a smaller number of kid- from Colorado about the combined use plantations. The longest survivor, a ney recipients did not reject their grafts. of azathioprine and prednisone, David child with biliary atresia, has now born Other crucial observations in our dog Hume began a third clinical program at her transplanted liver for 45 years. Al- studies had not been apparent under the the Medical College of Virginia. During though four new European centers were testing conditions of other laboratories. the next 2 years, nearly 50 more renal founded during this period, one year First, pretreatment with daily azathio- centers were founded in the United survival never exceeded 50% in any of prine for several weeks before canine States or were gearing up while a similar the five programs. Thus, liver transplan- kidney transplantation nearly doubled race was on in Europe. Development of tation continued to bear the label “feasi- survival compared with that when the these new centers was facilitated by my ble but impractical” until the advent of drug was begun on the day of operation. 1964 textbook, Experience in Renal Trans- cyclosporine in 1979 and our demon- Most importantly, acute rejections that plantation (20), based on personal labora- stration that the drug’s optimal use re- developed in dogs despite daily azathio- tory and clinical experience. Immuno- quired its combination with prednisone prine could almost always be reversed suppression with azathioprine and in the “steroids as needed” strategy by administration of large doses of pred- prednisone remained the worldwide originally used with azathioprine-prednisone. These readily reproducible ca- standard for nearly 20 years. nisone. Kidney recipients were the first nine findings were used to design clini- Encouraged by our kidney successes, I to benefit (25). In addition, 11 of our cal protocols in which prednisone was attempted five human liver replacements first 12 liver recipients treated with the added only to treat rejections that devel- between March and October 1963 by new baseline drug survived for more oped under azathioprine. using the same two drugs but with fore- than 1 year (26). This incremental use of the drugs ex- shortened pretreatment (21,22). The first At the end of December 1980, I moved posed two characteristic features of the recipient bled to death during the opera- from Colorado to Pittsburgh where the alloimmune response that ultimately tion. The longest survival of the next efficacy of the cyclosporine-based treat- were exploited for the transplantation of four patients was 23 d. All four of their ment was established for all trans- all kinds of organs with the aid of widely hepatic grafts functioned throughout and planted vital organs. In December 1981, variable immunosuppressants. These fea- had little evidence at autopsy of rejection the promising developments with em- tures made up the title of my report in or of preservation injury. Death had been phasis on liver replacement (27) were the October 1963 issue of Surgery, Gyne- caused by spreading infections that origi- made known to the United States Sur- cology, & Obstetrics (now Journal of the nated in the lungs. In addition, pul- geon General, C Everett Koop. Koop, American College of Surgeons) of the monary emboli had formed in and mi- with the support of President Ronald world’s first series of repetitively suc- grated to the lung from the veno-venous Reagan, initiated steps leading to a Con- cessful kidney transplantations: “The re- bypasses that had been an essential com- sensus Development Conference for

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liver transplantation that included input more than 3 decades earlier in dogs, as Organ alloengraftment was de facto from the four European centers. The well as the transplantation of the intes- a form of variable donor leukocyte conclusion on 23 June 1983 was that tine alone, were elevated to the status of chimerism–dependent tolerance, the liver transplantation had become a “clin- “clinical service.” The world’s longest completeness of which could be inferred ical service” rather than an experimental surviving multivisceral recipient, now a from the amount required of mainte- procedure. school teacher, has lived for 24 years nance immunosuppression. Contempora- The resulting worldwide stampede to after transplantation. Tacrolimus remains neously, Donna Przepiorka et al. reported develop liver transplant centers was the baseline immunosuppressant of from Seattle that essentially all bone mar- even more dramatic than that of kidney choice for all kinds of organ transplanta- row cell recipients previously thought to transplantation 2 decades earlier. Only 6 tion to the present day. have complete hematolymphopoietic cell years later, a 17-page article divided be- By the 1990s, organ transplantation replacement actually had a small resid- tween two October 1989 issues of the was widely acknowledged to be one of ual population of their own lymphoid New England Journal of Medicine (NEJM) the most significant medical advances of cells (35). Organ engraftment and bone began with the following statement: all time. It also was one of the most enig- marrow cell engraftment were nearly “The conceptual appeal of liver trans- matic. For >30 years, the unchallenged perfect mirror images. plantation is so great that the procedure dogma had been that donor leukocyte In contrast to the dominant HVG reac- may come to mind as a last resort for chimerism played no role in organ allo- tion of organ recipients, the GVH reac- virtually every patient with lethal he- engraftment. The consequence of this tion is dominant in bone marrow recipi- patic disease” (28,29). Most of the legiti- pervasive error was a never-ending ents whose immune system is weak or mate indications for transplant candi- search for chimerism-independent mech- deliberately weakened. Therapeutic fail- dacy were obvious, including anisms of organ alloengraftment. The fu- ure with either kind of transplantation inheritable disorders that had known tile exercise ended with our discovery of was explained by the inability to control biochemical explanations (for example, a small population of multilineage donor one, the other or both of the responses. Wilson disease). leukocytes (microchimerism) in all sur- Independently at almost the same In addition, liver transplantation as an viving organ recipients in whom a search time, Rolf Zinkernagel published formal instrument of clinical research received was done (33,34). proof that the T-cell response against worldwide attention in 1984 with the The microchimerism lay at the tipping noncytopathic microparasites could be case of Stormie Jones, a 6-year-old child point between immunity and tolerance exhausted and deleted (36). He then pro- with congenital hyperlipoproteinemia. (Figure 2, middle graphic). With our de- posed that clonal exhaustion-deletion Her heart had been irreparably damaged tection of the donor cells by sensitive im- and immune ignorance were the seminal by myocardial infarctions caused by the munocytochemical and molecular mechanisms of tolerance to noncyto- rapidly evolving coronary atherosclerosis probes, the connection was apparent be- pathic microorganisms (37). In this view, that typifies the lipid disorder. The cir- tween organ alloengraftment, the mouse disease carrier states (for example, hepa- cumstances surrounding her combined models of acquired tolerance, and clini- titis, cytomegalovirus) were manifesta- liver and heart replacement and my ra- cal bone marrow transplantation. Suc- tions of specific tolerance to the different tionale for proposing the drastic opera- cessful organ transplantation was ex- intracellular pathogens. The term “im- tion are described in the chapter titled plained by “responses of coexisting mune ignorance” referred to an antigen “The Little Drummer Girls” in my book, donor and recipient immune cells, each that fails to reach host lymphoid organs The Puzzle People: Memoirs of a Transplant to the other, causing reciprocal clonal ex- and is not therefore recognized to be Surgeon (30). pansion followed by peripheral clonal present. The phenomenon was first de- The revolution in all kinds of organ deletion” (33). scribed in the context of transplantation transplantation during the 1980s had The double immune response of organ by Clyde Barker and Rupert Billingham been driven by cyclosporine. However, transplantation is initiated by the migra- (38). by the time of our 1989 two-part NEJM tion of the allograft’s lymphoid cells With our mutual recognition that publication, our preclinical and clinical (“passenger leukocytes”) through vascu- donor leukocytes and intracellular studies of tacrolimus already had led to lar routes to host lymphoid tissues. pathogens are mobile antigen equiva- its replacement of cyclosporine as the There, the immunocompetent donor cells lents and that transplantation involved a baseline immunosuppressant (31,32). induce a host versus graft (HVG) anti- double immune response (host versus With tacrolimus, further improvements donor response while mounting a graft graft and graft versus host) that could be in survival were possible with liver, kid- versus host (GVH) response. If sufficient reciprocally exhausted and deleted, ney and ultimately all kinds of organ reciprocal clonal exhaustion is not Zinkernagel and I prepared a review for transplantation. In addition, the multivis- achieved, one cell population will de- NEJM. After describing a spectrum of ceral transplant procedures developed stroy the other. transplant scenarios from outright rejec-

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antigen-specific T cells induced at these lymphoid sites” (39 [quotation]; 40–45). These conclusions mandated a paradigm shift in transplantation immunology and in immunology overall. Given that balances between the quantity of mobile antigen and the number of antigen-specific T cells govern immunologic responsiveness and nonresponsive- ness, the actual role of transplant immunosuppression is simply to allow establishment of numerical supremacy of the donor leukocytes (Figure 2, middle graphic). Conditions favoring the mobile donor cells for bone marrow cell transplantation either preexist (that is, immune deficiency diseases) or are created in advance of transplantation by reduc- tion of global immune reactivity with irradiation or drugs. Exhaustion deletion of the impending donor-specific response is thereby made easier. In the contrasting treatment of organ transplant recipients, dominance of the donor cells relative to host antidonor T cells had been empirically achieved after rather than before transplantation. This step was accomplished with continuous immunosuppression that permitted clonal exhaustion and deletion of the host donor-specific response while avoiding immune injury to the allograft. The greatest threat of acute rejection (and risk of graft versus host disease) coin- cided with the mass migration of the Figure 2. Expressions of allotolerance. Top: Experimental and clinical models in which tolerance is associated with donor leukocyte macrochimerism. Bottom: Organ and composite organ’s passenger leukocytes during the tissue transplants for which alloengraftment is contingent on persistent donor leukocyte first few posttransplant weeks. This pe- microchimerism. Middle: Tolerance permutations defined as balances between the quan- riod also constituted a one-time-only tity of persisting donor leukocytes with access to host lymphoid organs (solid lines) and window of opportunity for nullification the number of antidonor T cells induced at these lymphoid sites (dotted lines). Stabilizing of the host-versus-graft and graft-versus- factors (asterisks) may include special cells (for example, T regulatory, suppressor), cy- host responses by reciprocal clonal tokine profiles, enhancing antibodies, graft secretions, and endogenous or exogenous cy- exhaustion-deletion (Figure 2). toprotective molecules. How continuous immunosuppression tilts the balance against In 2001, Zinkernagel and I pointed out donor-specific T cells is depicted by small down-directed open arrows. GVH, graft versus that the window would be closed to the host; HVG, host versus graft. extent that over-immunosuppression sub- verted the seminal tolerance mechanism tion to durable tolerance and their infec- infections, tumors, and self and against of clonal activation → exhaustion → tion analogs (39), we proposed two gen- xenografts and allografts” (39). The sec- deletion (41), leaving the recipient per- eralizable conclusions. ond conclusion was that “all . . . outcomes manently committed to heavy mainte- The first conclusion was that “the mi- [of adaptive immunity] are determined nance immunosuppression. Two thera- gration and localization of antigen are the by the balance reached between the peutic principles were proposed to governing factors in immunologic re- quantity of antigen with access to host reduce these self-defeating consequences: sponsiveness or unresponsiveness against lymphoid organs and the number of recipient pretreatment and minimal

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postoperative immunosuppression (41). 10. Starzl TE, Kaupp HA Jr, Brock DR, Linman JW. 30. Starzl TE. (1992) The Little Drummer Girls. In: The strategy was much the same as that (1961) Studies on the rejection of the transplanted The Puzzle People: Memoirs of a Transplant Surgeon. used in the canonical Colorado kidney homologous dog liver. Surg. Gynecol. Obstet. Pittsburgh, PA, University of Pittsburgh Press, 112:135–44. pp. 318–33. cases of 1962–1963 (18) and in conven- 11. Starzl TE, Kaupp HA Jr, Brock DR, et al.: (1962) 31. Starzl TE, et al. (1989) FK 506 for human liver, tional bone marrow transplant protocols. Homotransplantation of multiple visceral organs. kidney and pancreas transplantation. Lancet. Thus, insight about the meaning and Am. J. Surg. 103:219–29. 2:1000–4. mechanisms of tolerance derived from 12. Starzl TE, et al. (1973) The origin, hormonal nature, 32. Todo S, et al. (1990) Liver, kidney, and thoracic and action of hepatotrophic substances in portal organ transplantation under FK 506. Ann. Surg. the microchimerism discoveries has made venous blood. Surg. Gynecol. Obstet. 137:179–99. 212:295–305. it possible to interconnect all existing ex- 13. Starzl TE, Watanabe K, Porter KA, Putnam CW. 33. Starzl TE, et al. (1992) Cell migration, chimerism, amples of acquired transplantation toler- (1976) Effects of insulin, glucagon, and and graft acceptance. Lancet. 339:1579–82. ance (Figure 2). It has also set the stage insulin/glucagon infusions on liver morphology 34. Starzl TE, et al. (1993) Cell migration and for the more discriminating use in organ and cell division after complete portacaval shunt chimerism after whole-organ transplantation: the in dogs. Lancet. 1:821–5. basis of graft acceptance. Hepatology. 17:1127–52. recipients of the numerous currently 14. Francavilla A, Hagiya M, Porter KA, Polimeno L, 35. Przepiorka D, Thomas ED, Durham DM, Fisher L. available immunosuppressants (42,43). Starzl TE. (1994) Augmenter of liver regeneration (1991) Use of a probe to repeat sequence of the Y The possibility remains that appropri- (ALR): its place in the universe of hepatic growth chromosome for detection of host cells in periph- ately timed infusions of donor leukocytes factors. Hepatology. 20:747–57. eral blood of bone marrow transplant recipients. could facilitate the level of deletional tol- 15. Gandhi CR, et al. (2015) Liver-specific deletion of Am.J.Clin.Pathol. 95:201–6. augmenter of liver regeneration accelerates devel- 36. Moskophidis D, Lechner F, Pircher H, Zinker- erance achievable with the organ’s donor opment of steatohepatitis and hepatocellular car- nagel RM. (1993) Virus persistence in acutely in- passenger leukocytes alone (41–45). cinoma in mice. Gastroenterology. 148:379–391.e4. fected immunocompetent mice by exhaustion of 16. Billingham RE, Brent L, Medawar PB. (1953 ) Ac- antiviral cytotoxic effector T cells. Nature. DISCLOSURE tively acquired tolerance of foreign cells. Nature. 362:758–61. The authors declare that they have no 172:603–6. 37. Zinkernagel RM, Moskophidis D, Kundig T, 17. Main JM, Prehn RT. (1955) Successful skin homo- Oehen S, Pircher H, Hengartner H. (1993) Effec- competing interests as defined by Molec- grafts after the administration of high dosage X tor T-cell induction and T-cell memory versus pe- ular Medicine, or other interests that radiation and homologous bone marrow. J. Natl. ripheral deletion of T cells. Immunol. Rev. might be perceived to influence the re- Cancer Inst. 15:1023–9. 131:199–223. sults and discussion reported in this 18. Starzl TE, Marchioro TL, Waddell WR. (1963) The 38. Barker CF, Billingham RE. (1968)The role of affer- reversal of rejection in human renal homografts ent lymphatics in the rejection of skin homo- paper. with subsequent development of homograft tol- grafts. J. Exp. 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