Starzl, TE

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Peter Brian Medawar: Father of transplantation

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PETER BRIAN MEDAWAR: FATHER OF TRANSPLANTATION Thomas E. Starzl, M.D., PH.D., F.A.C.S. Reprintfrom Journal of the American College of Surgeons, March, 1995, Vol. 180,332-336 Copyright, 19%, by The American College of Surgeons PETER BRIAN MEDAWAR: FATHER OF TRANSPLANTATION Thomas E. Starzl, M.D., PH.D., F.A.C.S. MOST of the surgical specialities can be tracked to the creative vision of a surgeon. Transplan-tation is an exception. Here, the father of the field is succinctly defined in the dictionary as: "Peter Brian Medawar: a Brazilian born British Zoologist who at the age of 45 shared a 1960 Nobel Prize for his work on acquired immuno-logic tolerance" (1). Medawar was mysteriously overwhelming to many colleagues and observers, even when he was young. He was the son of a Lebanese father and an English mother-tall, athletic, abnormally handsome, hypnotically articulate in public, and politely cordial in his personal relations. In Sep-tember 1969, at the age of 54, he had the first of a series of strokes. These crippled him physi-cally but not in spirit. Although I saw Medawar often professionally and privately over a 22 year period, before and after he was disabled, this sporadic exposure was not enough to understand him. My sense is that no one did, except perhaps Jean, his wife for nearly 50 years. THE MEANING OF REJECTION Medawar's dazzling personality before and great courage after his strokes was inspirational, but his fame was based on the unique achieve-ment in 1953 captured by the terse dictionary mention of "acquired immunologic tolerance." The roots leading to this accomplishment had fed on the blood of war. More than 12 years earlier, the recently wed zoologist Medawar-24 years of age and fresh from graduate studies at Oxford University-was assigned to the service of the British surgeon, Dr. Thomas Gibson, to determine if skin allografts could be used to treat casualties from the Battle of Britain. First, in human studies with Gibson (2), and then with simple and logical rabbit experiments (3), Medawar showed that rejection of the skin was an immunologic phenomenon. This later was shown to be analogous to the cell-mediated de-From the Pittsburgh Transplantation Institute, University of Pitts-burgh, Pittsburgh, PA. Presented at the opening ceremony of the 80th Clinical Congress of the American College of Surgeons, October 10, 1994. Correspondence address: Dr. Thomas E. Starzl, 3601 Fifth Avenue, 4C Falk Clinic, Pittsburgh, PA 15213. 332 layed hypersensitivity that confers immunity to diseases such as tuberculosis (4, 5). The principal evidence in the early studies was that repetitive grafts from the same donor were rejected more rapidly with each successive attempt-the sensi-tization and donor specificity confirming an ear-lier clinical observations by Emil Holman of Stan-ford in skin-grafted burn victims (6). Once it was established that rejection was an immune reaction, strategies began to evolve to weaken the recipient immune system. By 1953, total body irradiation (7) and adrenal cortical steroids (8, 9) had been shown to delay skin rejection. However, this immunosuppressive effect was either minor if the animals survived, or lethal to the recipient if the grafts were spared. There was no margin of safety. THE BOMBSHELL PAPER In the resulting atmosphere of nihilism about clinical applications, a three and one-half page article by Billingham, Brent, and Medawar in the October 3, 1953 issue of Nature describing acquired tolerance (10), came as a blinding bea-con of hope. The three men had learned that donor splenocytes could be engrafted by their intravenous infusion into immunologically imma-ture mice in utero or perinatally. When these inoculated recipients matured, they could accept skin and other tissues from the donor (but from no other) mouse strain. The immune system of the recipients had been populated by the immunocytes of the donor, meaning that they were now chimeras. The race was on to convert this principle to humans. How-ever, the dark side of their accomplishment soon was revealed by the two younger members of Medawar's team, Billingham and Brent (11) and by the Dane, Simonsen (12). The engrafted do-nor cells could turn the tables and reject the defenseless recipient unless the tissue match was a good one. This was the dreaded graft versus host disease (GVHD) in which transplanted do-nor cells attacked the recipient skin, gastrointes-tinal tract, lungs, liver, and the bone marrow itself. Medawar's dream of 1953 was suddenly a nightmare. Or was it? Starzl: PETER BRIAN MEDAWAR: FATHER OF TRANSPLANTATION 333 SOLID ORGAN BONE MARROW Non-essential ~-=<;;;:;:;;;=--~;;;;I;IIIII:;I::;II"I""~qissue Match Kf-=T~~_f::"D-- Essential ----II+-m;;;iaD;w:=~KFo Toler ance Acceptance ... IKI;--~~~=~?---Uncommon ... ,.,;__--....;;..,...,..:m;..-----(Medawar) FIG. 1. The growth of bone marrow (right) and whole organ transplantation (left) from the seed planted by Peter Medawar during World War II. GVHD, Graft versus host disease. CLINICAL BONE MARROW TRANSPLANTATION On the contrary, the work took a straight line to clinical application (Fig. 1), after the dem-onstration by Prehn and Main (13) that similar tolerance could be induced in adult mice ren-dered immunologically defenseless by total body Two-Way Paradigm (Organ) \rnrnunosuppression GVH Mutual Natural Immunosuppression ~ ~K oo@ @ooo D~;D:;KK:K @o:® ~ o e ~KD @ @ © © @ © ~@~ '''. ;'. e:o;o@ " < •. ' @o~o@ :;~ Not Quite "r~; © Defenseless Graft .. Veto/Suppressor Cells rncon~f!llned L Cytokine Profile Changes ReCIpient Enhancing Antibodies I HVG (Rejection) ---I FIG. 2. Bidirectional mechanism of whole organ graft acceptance involving a graft-versus-host (GVH) reaction by the bone marrow-derived donor leukocytes in the graft that are pitted against the whole recipient immunologic apparatus (host-versus-graft [HVG], rejection). For conventional whole organ clinical transplantation, the recipient is not preconditioned. K~-- -------~--K--K 334 Journal of the American College of Surgeons . March 1995 . volume 180 Match Partial Mismatch Total Mismatch Mutual Natural Immunosuppression FIG. 3. Explanation with the two-way paradigm (Fig. 2) for the poor prediction by tissue matching (HLA) of out-come after whole organ transplantation. Rx, Treatment. irradiation before splenocyte (or later bone mar-row) infusion. The recipient conditioning, known as cytoablation, also could be accomplished with myelotoxic drugs. However, as Billingham, Brent, and Medawar had predicted (5), donor specific tolerance could be induced in humans without GVHD only if there was a good tissue (HLA) match. In 1968, 15 years after the epic Billingham, Brent and Medawar publication (l 0), Robert Good -Slowly Evolving Donor and Recipient-Specific Nonreactivity (Bidirectional Tolerance) FIG. 4. Strategy for donor leukocYle augmentation in re-cipients of whole organ allografts. The bone marrow is given at the time of the operative transplant procedure. (14) and Fritz Bach (15) reported the first two successful human bone marrow transplants. Both recipients of well matched bone marrow from blood relatives are still alive. This was a triumph in which the principal clinicians were internists, as summarized 25 years later in the acceptance speech by the 1990 Nobel Laureate Donnall Thomas (16). CLINICAL WHOLE ORGAN TRANSPLANTATION Surgeons pursued a quite different pathway. Rejection of whole organs was at first construed as a mirror image of the Billingham-Brent-Medawar model in that the leukocyte villains were the recipient rather than the donor immunocytes, and the defenseless allografts were the victims instead of the instruments of rejection. Literally accepted, this "one-way paradigm" provided no hope that whole organ transplantation would be feasible without first exchanging the bone marrow with that of the donor along the lines of the in-ternist strategy described above. Despite the consequent pessimistic predictions, Nobel Laureate Joseph Murray of Boston showed in January 1959 that renal transplantation was feasible-after sublethal total body irradiation of a fraternal twin recipient, but without the donor bone marrow (17). Five more examples of long survival (two with unrelated kidney donors) was reported in Paris during the next three years on the services of Jean Hamburger (18) and Rene Kuss (19). This looked like a different tree from Medawar's original seed (Fig. 1), in which success was called graft acceptance (not tolerance), was not depend-ent on good tissue matching, and did not have a threat of GVHD. Then, Murray and associates (20) showed that the same thing could be ac-complished in humans pharmacologically, using chronic therapy with azathioprine. This observa-tion came after extensive preclinical studies in dogs with Murray's young associate, Sir Roy CaIne of England, at the forefront (21). The clinical results with azathioprine were poor at first, no better than with total body irradiation (22). However, this changed dramatically in 1962 when azathioprine was systematically combined with prednisone at the University of Colorado (22) . Rejection that developed despite azathioprine treatment could be reversed surprisingly easily with prednisone. More importantly, the sub-sequent need for maintenance immunosuppres-sion with both drugs frequently declined. The Starzl: PETER BRIAN MEDAWAR: FATHER OF qoAK~pmlADeAqflk 335 same characteristic cycle of immunologic con-frontation and resolution was soon observed with the liver (23), ultimately with all other trans-planted whole organs, and with each of the in-creasingly potent new drugs introduced during the next 30 years. This reproducible chain of events constituted the cardinal principle on which the new and increasingly practical field of trans-plantation was based. Something had changed in the host, the graft, or both. But what? THE MEANING OF ORGAN "ACCEPTANCE" Medawar was perplexed. In 1964, commenting on the surprisingly good results of renal trans-plantation using azathioprine and prednisone in the Colorado series, and in the Richmond, Virginia, series of David Hume, Medawar wrote, " ... foreign kidneys do sometimes become acceptable to their hosts for a reason other than acquired tolerance in a technical sense . . ." (24). As usual, his insight was uncanny. Nevertheless, 30 years and a revolution in im-munology elapsed before the mystery of whole organ graft acceptance was resolved by study of the still-surviving early Colorado kidney and liver recipients. Donor leukocytes of bone marrow ori-gin, which are part of the structure of all organ grafts (the so-called "passenger leukocytes"), had migrated from the transplanted organs and were found in the skin, lymph nodes, blood-every-where throughout the recipients-as many as 30 years later (25, 26). In essence, a small fragment of disseminated extramedullary donor bone marrow (illustrated schematically in Figure 2 as a bone silhouette) had become assimilated into the overwhelmingly larger immunologic network of the host. Whole organ transplantation involved a mutually can-celing graft versus host as well as host versus graft reaction, with the ultimate development of reciprocal immunologic nonreactivity of both populations. The two components of transplan-tation immunology originally defined separately by Medawar and his colleagues, at long last, had been joined. The secret was that they were in-teractive. MILESTONES AND ENIGMAS REVISITED The two-way cancellation effect, illustrated in Figure 3 as a teeter-totter, explained how the tissue matching influence was blindfolded and rendered non predictive with whole organ trans-plantation, explained the characteristic cycle of FIG. 5. Peter Brian Medawar (1915-1987). cnsIS and recovery that we see in our patients postoperatively, and made it understandable why GVHD usually does not occur after liver, intes-tinal, multivisceral, and heart and lung trans-plantation. It also explained why all whole organs have the inherent capability of tolerance induc-tion. This had long been a contention of Paul Russell (27), the first American surgeon to work with Medawar. . In closing the once vast gap between the bone marrow and whole organ transplantation fields, the two-way paradigm of transplantation immu-nology developed in 1992 (25) also had exposed a perioperative window of opportunity, during which unaltered HLA mismatched bone marrow can be given safely to whole organ recipients without recipient cytoablation or any deviation from the standard immunosuppressive strategies developed empirically 30 years earlier (Fig. 4). During the last 2 years, gross chimerism has thereby been produced routinely (28)-in the first cohort of patients to undergo HLA mis-matched whole organ transplantation with the reasonable prospect of eventually becoming drug free. This, of course, was the final fulfillment of Medawar's dream. It came five years after his death in 1987 at the age of 72 years. 336 Journal of the American College of Surgeons . March 1995 . Volume 180 A MEDICAL GALILEO At the Transplantation Society Congress in Paris in 1992, I noted that almost 400 years to the day previously Calileo had arrived to his faculty position at the University of Padua. With a tele-scope constructed by himself, he began the in-quiries that defined the mysterious universe and resulted in man walking on the moon. Our Calileo was Peter Medawar, whose first probes into the biologic meaning of rejection and the universe of transplantation took place about 14 percent of the time from now, back to those medieval days. Armed with dissecting scissors, a few rabbits and mice in a dilapidated London laboratory-and a remarkable brain that stayed vital even as its motor function was cruelly removed piece-meal-this zoologist founded a new field that crossed all specialty barriers and blurred, as no one ever had before, the distinction between basic and clinical science. Small wonder that we re-member so vividly and fondly the proud face illustrated in Figure 5. REFERENCES 1. Medawar-Sir Peter Brian 1915-1987. The American Heritage Dictionary of The English Language, 3rd Edi-tion, p 1120. Boston: Houghton Mifflin Company, Bos-ton, 1992. 2. Gibson, T., and Medawar, P. B. The fate of skin ho-mografts in man. ]. Anatomy, 1963, 77: 299-310. 3. Medawar, P. B. The behavior and fate of skin autografts and skin homografts in rabbits.]. Anat., 1944, 78: 176-199. 4. Mitchison, N. A. Passive transfer of transplantation im-munity. Proc. R. Soc. Lond. (Bio!.), 1954, 141; 72-87. 5. Billingham, R., Brent, L., and Medawar, P. Quantitative studies on tissue transplantation immunity. II. The ori-gin, strength and duration of actively and adoptively acquired immunity. Proc. R. Soc. Lond. (Bio!.), 1954, 143: 58-80. 6. Holman, E. Protein sensitization in isoskin grafting; is the latter of practical value? Surg. Gyneco!. Obstet., 1924, 38: 100-106. 7. Dempster, W. ]., Lennox, B., and Boag,]. W. Prolon-gation of survival of skin homotransplants in the rabbit by irradiation of the host. Br. J. Exp. Patho!., 1950, 31: 670-679. 8. Billingham, R. Eo, Krohn, P. L., and Medawar, P. B. Effect of cortisone on survival of skin homografts in rabbits. B. M. J., 1951, 1: 1157-1163. 9. Morgan,]. A. The influence of cortisone on the survival of homografts of skin in the rabbit. Surgery, 1951, 30: 506-515. 10. Billingham, R. Eo, Brent, L., and Medawar, P. B. "Actively acquired tolerance" of foreign cells. Nature, 1953, 172: 603-606. 11. Billingham, R., and Brent, L. A simple method for inducing tolerance of skin homografts in mice. Trans-plant. Bull., 1957, 4: 67-71. 12. Simonsen, M. The impact on the developing embryo and new born animal of adult homologous cells. Acta Path. Micro. Scand., 1957, 40: 480-500. 13. Main,]. M., and Prehn, R. T. Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow. J. Nat!. Cancer Inst., 1955, 15: 1023-1029. 14. Gatti, R. A., Meuwissen, H. J., Allen, H. D., and others. Immunological reconstitution of sex-linked lymph open-ic immunological deficiency. Lancet, 1968, 2: 1366-1369. 15. Bach, F. H. Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet, 1968, 2: 1364-1366. 16. Thomas, E. D. Allogeneic marrow grafting-A story of man and dog. In History of Transplantation: Thirty-Five Recollections. Edited by P. I. Terasaki. pp. 379-394. U. C. L. A. Press, 1991. 17. Merrill,]. P., Murray,]. E., Harrison,]. H., and others. Successful homotransplantation of the kidney between non-identical twins. N. Engl. J. Med., 1960, 262: 1251-1260. 18. Hamburger,]., Vaysse,]., Crosnier, J., and others.Renal homotransplantation in man after radiation of the re-cipient. Am. J. Med., 1962, 32: 854-871. 19. Kuss, R., Legrain, M., Mathe, G., and others. Homolo-gous human kidney transplantation. Experience with six patients. Postgrad. Med. J., 1962, 38: 528-531. 20. Murray,]. E., Merrill, J. P., Harrison, ]. H., and others. Prolonged survival of human-kidney homografts by im-munosuppressive drug therapy. N. Engl. J. Med., 1963, 268: 1315-1323. 21. CaIne, R. Y. Inhibition of the rejection of renal ho-mografts in dogs with purine analogues. Transplant. Bull., 1961, 28: 445. 22. Starzl, T. E., Marchioro, T. L., and Waddell, W. R. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg. Gynecol. Obstet., 1963, 117: 385-395. 23. Starzl, T. E., Marchioro, T. L., Porter, K. A., and others. Factors determining short- and long-term survival after orthotopic liver homotransplantation in the dog. Sur-gery, 1965, 58: 131-155. 24. Medawar, P. B. Transplantation of tissues and organs: introduction. Br. Med. Bull., 1965, 21: 97-99. 25. Starzl, T. E., Demetris, A. ]., Murase, N., and others. Cell migration, chimerism, and graft acceptance. Lan-cet, 1992, 339: 1579-1582. 26. Starzl, T. E., Demetris, A. ]., Trucco, M., and others. Cell migration and chimerism after whole organ trans-plantation: the basis of graft acceptance. Hepatology, 1993, 17: 1127-1152. 27. Russell, P. S., Chase, C. M., Colvin, R. B., and Plate, J. M. D. Kidney transplants in mice. An analysis of the immune status of mice bearing long-term H-2 in-compatible transplants. J. Exp. Meei., 1978, 147: 1449-1468. 28. Fontes, P., Rao, A., Demetris, A. ]., and others. Aug-mentation with bone marrow of donor leukocyte mi-gration for kidney, liver, heart, and pancreas islet trans-plantation. Lancet, 1994, 344: 151-155. 