|
Preface
"If gold medals and prizes were awarded to institutions instead of in-dividuals, the Peter Bent Brigham Hospital of 30 years ago would have qualified. The ruling board and administrative structure of that hospital did not falter in their support of the quixotic objective of treating end-stage renal disease despite a long list of tragic failures that resulted from these early efforts - leavened only by occasional encouraging notations such as those in the identical twin case. Those who were there at the time have credited Dr. George Thorn, Chairman of Medicine and Dr. Francis D. Moore, Chairman of Surgery, with the qualities of leadership, creativity, courage, and unselfishness that made the Peter Bent Brigham Hospital a unique world resource for that moment of history. (1 )"
Introduction
Although renal transplantation had been performed sporadically during the first half of this century (2,3), planned programs for human organ transplantation started only in the late 1 940s. At that time clinicians in Paris, London, Edinburgh, and Boston began renal transplantation in un-modified human recipients in spite of the warnings and pessimistic predictions of the many scientists and experienced clinicians.
Many big-scientists had difficulty under-standing the determined optimism of clinicians who were willing to evaluate any type of treatment which might possibly help these terminally ill uremic patients, most of whom were young and otherwise healthy. Tantalizing reports of functioning human renal transplants had surfaced from time to time (4-6); these hints of success were fur-ther encouragement.
In this lecture I will focus on the renal transplant program of the Peter Bent Brigham Hospital (now the Brigham and Women's Hospital) in Boston and explain how this small hospital became involved in transplantation. The medical and surgical services, along with the Department of Pathology under Dr. Gustave J. Dammin, led the way and ultimately renal transplanta-tion involved most of the hospital in some way or other.
The full story of successful organ transplantation in man weaves together three separate pathways: the study of renal disease, skin grafting in twins, and surgical determination. A leitmotif permeates each of these pathways, ie, a single event or report was critical for medical progress.
Renal Disease
The first two Physicians-in-Chief, the Hersey Professor at Harvard in their day, Dr. Henry Christian and Dr. Soma Weiss, had a major interest in renal disease. When Dr. Thorn succeeded Dr. Weiss in 1943 he and his associate Dr. James O'Hare con-tinued this interest, especially the relation-ship of renal disease to hypertension. After World War II Dr. Thorn invited Dr. Willem Kolff from The Netherlands to Boston to demonstrate a dialysis machine which he had developed during his forced confine-ment by the Germans. DE Carl W. Walter helped to improve the design and thus the Kolff-Brigham "artificial kidney" was devised. It was first used in patients in 1948 and set the stage for extensive new innovative approaches to both acute revers-ible renal disease and end-stage failure.
Because renal dialysis provided only temporary improvement for the patient, it was logical to seek a more permanent therapy. (Chronic dialysis was not developed until 10 years later by Schribner in Seattle). In the late 1 940s during Grand Rounds at the Brigham, I was astounded to hear Dr. Thorn say, "The best way to treat hypertension is to remove both kidneys!” The entire audience gasped. The seed for the Brigham renal transplant program had been planted.
Skin Grafting in Twins
This thread in the story involves the biological phenomena of monozygotic and dizygotic twinning. The monozygotic, "iden-tical" twin experience starts with the treat-ment of burns, the dizygotic, "nonidentical” twin story begins with freemartin cattle (the spelling varies: one word, two words, or hyphenated).
In 1932 Dr. E. Padgett of Kansas City reported the use of skin allografts from fami-ly and unrelated donors to cover severely burned patients who had insufficient un-burned donor sites for the harvesting of autografts. Although none of these skin al-lografts survived permanently, many would remain long enough to control infection and fluid loss and thus gain time for the donor sites to reepithelialize. It was difficult to determine accurately the duration of sur-vival of any one allograft; some seemed to melt away slowly and be replaced by ad-jacent skin, others seemed to be rejected rapidly (7).
Skin grafts from family members seemed to survive longer than those from unrelated donors. But even after observing hundreds of skin allografts, one could not be certain about their survival time. One certainty was established when Dr. J.B. Brown of St. Louis in 1937 achieved per-manent survival of skin grafts exchanged between monozygotic twins (8).
This single observation, although restricted in application, was the only ray of light in the problem of tissue and organ re-placement until Gibson and Medawar demonstrated that a second allograft from the same donor was rejected more rapidly than the first (9). This clear description of the ”second set" phenomenon established that the rejection process was not im-mutable; instead it implied an allergic or im-munological process which potentially might be manipulated.
The dizygotic twin story starts with John Hunter's description of freemartin cat-tle in 1779 (10). Freemartins are twin came in which the male is normal and the female sterile. Hunter cites Roman descriptions of the phenomenon and then described the physical characteristics of several pairs he had collected in England.
The trail does not appear again until 1917 when Lillie, not content with mere descriptions, dissected the placental of several pairs of freemartin came and noted the placental intermingling of blood between these differently sexed twins (11). Thirty years elapsed before Owen published on the tolerogenic consequences of this placental intermingling of circulation (12). Following this Anderson in 1949 reported successful skin allografts between the freemartin and the normal male (13).
The freemartin story culminates in the report of Billingham, Brent and Medawar describing an acquired immunological tolerance produced by neonatal injection of donor cells into a future allograft recipient (14). They indicate that it was the ex-perimental counterpart to Owen's naturally occurring model. Although not applicable to the clinical situation, their experimental breeching of the immunological barrier was another impetus for optimism in the problem so many considered hopeless.
Sir Michael Woodruff, the pioneer transplant surgeon in Edinburgh, confirmed the freemartin concept in man when he found a pair of twins, one male the other female, who shared elements of different red cell types. Postulating a shared placen-tal circulation between the two, he cross skin grafted them successfully (15).
Surgical Determination
In 1912, Dr. A. Carrel received a Nobel Prize "in recognition of his work on vascular suture and the transplantation of blood ves-sels and organs." He clearly recognized the difference in the survival times between autografts and allografts in experimental animals, but he did not conceptualize rejec-tion as distinct from other graft-destroying processes.
Quinby in 1916 used the canine renal autograft model to study the effect of dener-vation on renal function (16). Mann and Williamson a decade later noted the dif-ferent survival times between canine renal autografts and allografts (17,18), but like Carrel, they did not pursue the long-term fate of the autografts. After World War II Dempster (19) and-Simonsen (20) publish-ed extensively on canine renal transplanta-tion concentrating on the biology and biochemistry of allograft rejection. They demonstrated that skin and kidney allografts possess a common antigen which could sensitize a recipient to a subsequent al-lograft of either tissue from the same donor. In these reports, there was the tacit as-sumption that renal autograft function would deteriorate ultimately, possibly because of lack of nerve supply and/or Iymphatics.
From a physiological view, if human renal transplantation were to be successful, we needed to establish that renal transplants in the absence of an im-munological barrier could function per-manently. In the course of many laboratory experiments on canine renal transplanta-tion, I had developed a reproducible opera-tion using intra-abdominal vascular anastomoses and a uretero-cystostomy for urinary drainage, placing the kidney in the lower abdomen. This has become the universal renal transplant procedure since that time. Complete functional studies of some of these autografted kidneys two years after transplantation proved them to be completely normal (21).
The Three Trails Merge
These three trails merged at the Peter Bent Brigham in the late 1 940s. All the ele-ments for a sound renal transplant program were in order: experienced knowledge in renal disease, availability of dialysis, and skilled imaginative surgeons. To minimize morbidity, the first allografts in these un-modified human recipients were added as a third kidney in the thigh under local anes-thesia. Dr. David Hume was the surgeon for these patients and he anastomosed the renal vessels of the graft to the femoral ves-sels of the recipient. Urine was collected in a bag from a skin ureterostomy (22).
Several of these unmodified human al-lografts functioned better than experimental canine allografts would have predicted. Possible explanations were an immunosup-pressive effect of uremia or a beneficial ef-fect of acute tubular necrosis which occurred regularly in these inadequately preserved donor kidneys. One thigh transplant functioned for almost six months with return of the patient's biochemical profile and blood pressure to normal, demonstrating that transplants could rectify the pathophysiologic disorder of renal insufficiency.
The very first renal transplant in 1945 at the Brigham deserves special comment. The patient was a young woman in renal failure following obstetrical complications. The pur-pose of the transplant was to provide temporary renal function until her own kidneys recovered from acute tubular necrosis. Dr. Thorn recalls his inability to obtain permission to have the patient transferred to a regular operating room (this was prior to Dr. Moore's tenure) so the operation was performed on the old E-Second Ward by Dr. Charles Hunfnagel, then a Research Fellow working on vas-cular grafts, Dr. Earnest Landsteiner, then Chief Resident in Urology, and Dr. David Hume, then Assistant Resident in Surgery. The donor kidney was anastomosed in the antecubital space under local anesthesia using a cutaneous ureterostomy.
According to Dr. Robert J. Glaser, who was Assistant Resident on the medical ser-vice at that time, "secretion of urine was minimal, and certainly did not, 'rescue the woman from her crisis.' The kidney func-tioned poorly and only transiently, and the patient continued to have a stormy course, although fortunately, despite our lack of un-derstanding at the time of how best to treat renal shutdown, she ultimately did respond and she left the hospital with normal renal function and in good health.”
Dr. Glaser further reports that her happy state was short-lived because she died a few months later of fulminating hepatitis secondary to pooled plasma in-fusions which she had received in the course of her treatment. Interestingly, Dr. Glaser still recalls taking care of the patient whose kidney was ultimately used as the donor transplant. "The patient had dissemi-nated lupus erythematosus and had been in the Brigham many times. Although in patients with advanced lupus the kidney is usually badly damaged, in this particular case renal manifestations were relatively limited, and when her kidney became avail-able it was therefore used (23)."
The Identical-Twin Patient
In the fall of 1954, Dr. Donald Miller of the United States Public Health Service telephoned Dr. Merrill in order to refer a patient with severe renal disease. Moreover, Dr. Miller suggested there might be the opportunity for transplantation of a kidney because the patient had a healthy twin brother. Needless to say, the transplant team was interested in the pos-sibility of transplanting a genetically compatible kidney. Cross skin grafting established genetic identity, renal disease was brought under control with medications and dialysis, and we were ready to apply our laboratory-tested surgical technique to man.
The only remaining problem was the ethical decision concerning the removal of a healthy organ from a normal person for the benefit of someone else. For the first time in medical history a normal healthy person was to be subjected to a major surgical operation not for his own benefit.
After many consultations with experienced physicians within and outside the Brigham and with clergy of all denominations, we felt it reasonable to offer the operations to the recipient, the donor, and their family. We discussed in detail the preparations, anesthesia, operations, pos-sible complications, and anticipated result.
At the conclusion of our last preopera-tive discussion, the donor asked whether the hospital would be responsible for his health care for the rest of his life if he decided to donate his kidney. Dr. Harrison, the surgeon for the donor, said, "Of course not." But he immediately followed with the question, "Ronald, do you think anyone in this room would ever refuse to take care of you if you needed help?" Ronald paused, and then understood that his future depended upon our sense of professional responsibility rather than on legal assuran-ces.
Once the patients and the team decide to proceed with the transplant, an extra professional burden falls on the surgeon performing the donor nephrectomy because his patient is expected to survive normally. In contrast, the surgeon performing the transplant is operating on a patient other-wise doomed to die, and the nephrologist caring for these critically ill patients cannot be faulted for failure to cure.
Postoperatively the transplanted kidney functioned immediately with a dramatic im-provement in the patient's renal and cardiopulmonary status. This spectacular success was a clear demonstration that organ transplantation could be life saving. In a way, it was spying into the future be-cause we had achieved our long-term goal by bypassing, but not solving, the issue of biological incompatibility (24,25).
Subsequent Laboratory and Clinical Study
The impact was worldwide and stimu-lated widespread laboratory attempts to breech the immunological barrier. Experimental protocols included total body X-ray treatment followed by marrow infusion, mmunoparalysis by consecutive graftings, immunological enhancement or adaptation by prior exposure of the host or graft to an-tigen, matching of donor and recipient by red or white cell typing, and the use of drugs such as toluene and nitrogen mus-tard.
We continued with both clinical and laboratory studies. In a series of volunteer uremic patients, we noted a prolonged but not permanent survival of skin allografts, suggesting the uremic state itself was im-munosuppressive (26). In several series of dogs we tried without success to establish a state of renal insufficiency by partial removal of renal mass, infusion of toxins directly into the renal artery, temporary is-chemia, and/or thermal insult. Attempts to prolong graft survival by treating the host with steroids and/or anticoagulants also failed (27).
To study the "X-ray marrow" protocol, which seemed to have the best potential for human application, we used mice and rab-bits. Using sublethal or lethal doses of total body X-ray, followed by marrow infusions from single or multiple-donors, we were able to obtain a limited number of long-surviving skin allografts (28).
Simultaneously during the 1 950s we transplanted several more sets of identical twins. One twin transplanted in 1956 com-pleted a pregnancy two years later (29). She is now a grandmother and the longest living renal transplant recipient. Her donor, also a grandmother, likewise is in perfect health. Initially regarded as a unique occur-rence, the identical twin situation has con-tinued to reappear worldwide. It is estimated that at least 50 patients have now received transplants from their identical twins.
Several patients were referred during these years suffering from accidental loss of a solitary kidney. Because we had obtained limited encouraging laboratory results, it seemed reasonable to treat some of these patients with an "X-ray-marrow" protocol, ie, total body X-ray followed by marrow in-fusion and a renal allograft. In most of the patients, the transplanted kidneys func-tioned immediately and continued to do so for several weeks, but in only one of 12 patients did function persist beyond three months.
The one success was our third patient, a dizygotic twin who received a sublethal, non-marrow-requiring, dose of total body X-ray, given by Dr. James B. Dealy, followed by a kidney graft from his twin brother in 1959. He recovered after a difficult compli-cated postoperative course; he sub-sequently led a full active normal life until he died of cardiac problems 25 years later. He was the world's first successful fraternal twin renal allograft and was the enticement and stimulus for us to continue this method of procedure until drugs became available (30-32). The Hamburger group in Paris subsequently had a similar success with a dizygotic twin recipient following sublethal X-ray treatment.
The First Successful Cadaveric Transplant in Man
Although we began our first experi-ments in rabbits using Thio-TEPA as a sub-stitute for total body X-ray treatment in 1958 (33), the real breakthrough came with the introduction of immunosuppressive drugs by Schwartz and Dameshek in 1959 (34). They prevented rabbits from producing an-tibody against human serum albumin by treating them for two weeks with the an-timetabolite, 6-mercaptopurine. This “drug induced tolerance" remained after drug treatment was stopped, even though the animals could react normally against another protein antigen, bovine gamma globulin. Thus the tolerance seemed to be specific for an antigen introduced at the time of drug administration. Roy Calne in London (35) and Charles Zukoski in Virginia (36) tested this drug in the canine renal transplant model and had encouraging results.
On the advice of Sir Peter Medawar, in 1960 Calne came to Boston to work with me in Dr. Francis D. Moore's Department at the Harvard Medical School and the Peter Bent Brigham Hospital. Calne introduced us to Dr. Hitchings and Dr. Elion of the Burroughs -Welcome Laboratories who became en-thusiastic collaborators. Following Calne's arrival and with the use of drugs supplied by Dr. Hitchings the improvement in allograft survival was rapid and dramatic. Soon we had many bilaterally nephrectomized dogs in our laboratory living on solitary renal al-lografts. Some survived for months, even-tually for years. One produced a normal litter sired by a drug-treated allografted male. One dog recovered from a severe osteomyelitis of the mandible, indicating he was not an immunological cripple, a state we feared might result from prolonged use of the drugs (37). During this time we were testing other drugs from Hitchings and Elion, who were frequent visitors and knew most of our dogs by name. The experimen-tal drug, BW-322, the imidazole derivative of 6-mercaptopurine, seemed to have the best therapeutic index. This drug is now known as azathioprine, or Imuran, and was used throughout the world to support organ transplantation for 20 years. Now newer drugs are available and under study to ex-tend their usefulness and diminish toxicity.
Reassured by these results, we decided to use these drugs in humans for immunosuppression. The first renal transplant recipient to receive azathioprine was an adult transplanted with an unrelated kidney in March 1961. The transplant func-tioned well for over one month, but the patient died of drug toxicity because the dosage required in dogs was toxic for man.
Our second patient also died of drug toxicity even though we halved the dose used for our first patient. For the first time in our experience we were able to reverse the rejection process. When we discontinued the drug because of leucopenia, rejection started to occur. As his leucopenia im-proved, we restarted the drug which reversed the rejection process and his renal function improved. Nevertheless he did succumb to sepsis after a month (38).
Our third patient, transplanted in April 1962, was treated with azathioprine follow-ing a cadaveric renal allograft. He survived over one year and was the world's first successful unrelated renal allograft. We reported these results in the New England Journal of Medicine (39) and a case report in the Journal of the American Medical As-sociation followed (40). Dr. Willard Good-win, at the University of California in Los Angeles, almost immediately introduced the use of corticosteroids as a further ad-junct to the treatment (41). Subsequently several transplantation groups worldwide began their own productive transplantation programs.
By 1965, one-year survival rates of al-lografted kidneys from living related donors were approaching 80 percent and from cadavers 65 percent. Regional and national donor procurement programs were estab-lished along with an International Renal Transplant Registry (42). Optimism and enthusiasm were high as new drugs and other methods of immune suppression were tested along with refinements in tissue typing and improved organ preservation. Antilymphocyte serum and globulin prepared in horse, sheep, and rabbit along with thoracic duct drainage of Iymphocytes were among the more promising regimens tested. Currently it is estimated that more than 200,000 human renal transplants have been performed worldwide.
Other Organs
The success with renal allografts naturally led to attempts to transplant other organs. Moore developed the surgical technique for orthotopic canine liver transplantation (43), the model procedure used by Starzl for first successful human liver al-lografts (44). Calne, returning to Cambridge, England, also developed an ex-tensive human liver transplantation ex-perience. For almost 15 years Starzl and Calne performed the vast majority of the world's human liver transplants (45). Today the operation is second only to kidney in frequency and is performed universally.
The next organ to be transplanted was the heart. Lower and Shumway had developed the surgical technique in dogs in 1961 and were planning a careful program for cardiac transplantation in humans. After Barnard's first human cardiac transplant in 1967, many other cardiac surgeons with lit-tle or no immunological background rapidly accumulated large numbers of heart transplanted patients, only to witness them all die of rejection within a few months. This period between 1968 to 1970 was undoub-tedly transplantation's darkest hour. The sole redeeming feature in heart transplanta-tion was the continuation of Shumway's pro-gram at Stanford which achieved permanent success in 1970 (46). Today with the development of newer drugs, cardiac transplantation is a recognized and ac-cepted form of treatment.
Single- and double-lung transplantation have followed, as well as combined heart-lung transplants. Transplantation of the pancreas, with or without an accompanying renal graft, is commonly done. Multiple .:organ transplants in combination with liver and parts of the intestinal tract have also been successful. In 1989, there were 8,890 kidney, 2,160 liver, 1,673 heart, 413 pancreas, and 67 heart-lung transplants performed in the United States alone (47).
Ironically, allografts of skin, the tissue used classically in most of the early studies of transplantation, have proven to be the most difficult to transplant. Skin is the ul-timate protection of the individual against the environment and therefore over the ages has evolved into our strongest barrier against foreign proteins. The earlier conventional wisdom was that the fate of skin allografts predicted the results of other transplants. Commenting on the contrast-ing survival rates of skin and kidney al-lografts in immunosuppressed dogs, Medawar proclaimed with his customary flair, that the success of organ transplanta-tion has "overthrown the doctrinal tyranny of skin grafts (48)."
The Future
Although thousands of young lives have already been saved by the use of various immunosuppressive regimens. serious complications still occur as a result of the treatment. The ultimate aim is to achieve an immunological tolerance be-tween donor and recipient, eliminating en-tirely the need for drugs. There are hints both in the laboratory (49) and in man (50) that the liver itself can produce tolerogenic factors which may reduce or eliminate the need for immunosuppressive drugs. Dis-covering or uncovering naturally occurring immunosuppressive substances seems likely. It surely is as probable as the prospect of obtaining successful organ transplants was 45 years ago.
REFERENCES
1. Starzl TE. The landmark identical twin case. JAMA 1984; 251:2572.
2. Moore FD. Transplant, The Give and Take of Tissue Transplantation. Simon and Schuster, New York, 1972; 66.
3. Groth CE. Collective review. Landmarks in clinical renal transplantation. Surg Gynecol Obstet 1972; 134:323.
4. Lawlor RH, West JW, McNulty PH, et al. Homotransplantation ot the kidney in the human: supplemental report of a case. JAMA 1951; 147:45.
5. Kuss R, Teinturier J, Milliez P Quelques es-sais de greffe du rein chez l'homme. Mem Acad Chir 1951; 77:755.
6. Michon L, Hamburger J, Economos N, et al. Une tentative de transplantation renale chez l'homme: aspects medicolaux et biologi-ques. Presse Med 1953; 61:1419.
7. Padgett EC. Is iso-skin grafting practicable? South Med J 1932; 25:895.
8. Brown JB. Homografting of skin: with report of success in identical twins. Surgery 1937; 1:558.
9. Gibson T, Medawar PB. Fate of skin homografts in man. J Anat 1942; 77:299.
10. Hunter J. On the free martin. R Coll Surg XX; Feb. 25,1779.
11. Lillie FR. The theory of the free-martin. Science 1916; 43:611.
12. Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945; 102:400.
13. Anderson D, Billingham RE, Lamkin GH, et al. Use of skin grafting to distinguish be" tween monzygotic and dizygotic twins in cat-tle. Heredity 1951; 5:379
14. Billingham RE, Brent L, Medawar PB. Ac-tively acquired tolerance of foreign cells. Nature 1953; 172:603.
15. Woodruff MFA, Lennox B. Reciprocal skin grafts in a pair of twins showing blood chimerism. Lancet 1959; 2:476.
16. Quinby WC. The function of the kidney when deprived of its nerves. J Exp Med 1916; 23:535.
17. Williamson CS. Further studies on the transplantation of the kidney. J Urol 1926; 16:231.
18. Steriofl S, Rucker-Johnson N. Frank C. Mann and transplantation at the Mayo Clinic. Mayo Clin Proc 1987; 62:1051.
19. Dempster WJ. The homotransplantation of kidneys in dogs. Br J Surg 1953; 40:477.
20. Simonsen M, Buemann J, Gammeltoft A, et al. Biological incompatibilty in kidney transplantation in dogs. Acta Pathoi Microbiol Scand 1953; 32:1.
21. Murray JE, Lang S, Miller BJ, et al. Prolonged functional survival of renal autografts in the dog. Surg Gynecol Obstet 1956; 103:15.
22. Hume DM, Merrill JP, Miller BF, et al. Ex-periences with renal homotransplantation in the human: report of nine cases. J Clin In~ vest 1955; 34:327.
23. Glaser RJ. Footnotes to kidney transplant history. Focus: March 31, 1968. Harvard University News Office for the Medical Area, Boston, 1968; 8.
24. Murray JE, Merrill JP, Harrison JH. Renal homotransplantation in identical twins. Surg Forum 1955; 6:432.
25. Merrill JP, Murray JE, Harrison JH, et al. Successful homotransplantation of the human kidney between identical twins. JAMA 1956; 160:277.
26. Dammin GJ, Couch NP, Murray JE. Prolonged survival of skin homografts in uremic patients. Ann NY Acad Sci 1957; 64:967.
27. Lang S, Murray JE, Miller BF. Homotransplantation of ischerrlic kidneys into dogs with experimentally produced im-pairment of renal function. Plast Reconstr Surg 1956; 17:211.
28. Wilson RE, Dealy JB, Sadowsky N, et al. Transplantation of homologous bone mar-row and skin from common multiple donors following total body irradiation. Surgery 1959; 46:261.
29. Murray JE, Merrill JP, Harrison JH. Kidney transplantation between seven pairs of iden-tical twins. Ann Surg 1958; 148:343.
30. Murray JE, Merrill JP, Dammin GJ, et al. Study of transplantation immunity after total body irradiation: clinical and experimental investigation. Surgery 1960; 48:272.
31. Merrill JP, Murray JE, Harrison JH, et al. Successful homotransplantation of the kid-ney between non-identical twins. N Engl J Med 1960; 262:1251.
32. Murray JE, Merrill JP, Dammin GJ, et al. Kidney transplantation in modified recipients. Ann Surg 1962; 156:337.
33. Porter KA, Murray JE. Homologous marrow transplantation in rabbits after triethylenethiophosphoramide (Thio-TEPA). AMA Arch Surg 1958; 76:908.
34. Schwartz R, Dameshek W. Drug-induced immunological tolerance. Nature 1959; 183:1682.
35. Calne RY. The inhibition of renal homograft rejection in dogs by 6-mercaptopurine. Lan-cet 1960: 1:417.
36. Zukoski C, Lee HM, Hume DM. The prolon-gation of functional survival of canine renal homografts by 6-mercaptopurine. Surg Forum 1960; 11:470.
37. Calne RY, Alexandre GPJ, Murray JE. A study of the effects of drugs in prolonging survival of homologous renal transplants in dogs. Ann NY Acad Sci 1962; 99:743.
38. Murray JE. Balankura O, Greenburg JB, et al. Reversibility of the kidney homograft reaction by retransplantation and drug therapy. Ann NY Acad Sci 1962; 99:768.
39. Murray JE, Merrill JP, Harrison JH, et al. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N Engl J Med 1963; 268:1315.
40. Merrill JP, Murray JE, Takacs F. Successful transplantation of kidney from a human cadaver. JAMA 1963; 185:347.
41. Goodwin WE, Kaufman JJ, Mims MM, et al. Human and renal transplantation. I. Clinical experiences with six cases of renal transplantation. J Urol 1963; 89:13.
42. Murray JE, Barnes BA, Atkinson JC. Fifth report of the human kidney transplant registry. Transplantation 1967; 5:752.
43. Moore FD, Smith LL, Burnap TK, et al. One stage homotransplantation of the liver fol-lowing total hepatectomy in dogs. Transplant Bu111959; 6:103.
44. Starzl TE, Groth CG, Brenschneider L, et al. Orthotopic transplantation of the human liver. Ann Surg 1968; 168:392.
45. Calne RC, Williams R. Liver transplantation in man. I. Observations on technique and organization in five cases. Br Med J 1968; 4:535.
46. Dong E, Griepp RB, Stinson EB, et al. Clini-cal transplantation of the heart. Ann Surg 1972; 176:503.
47. U.S. Dept of Health and Human Services, Division of Organ Transplantation, Rockville, MD.
48. Medawar PB. Transplantation of tissues and organs: introduction. Br Med J 1965; 21:97.
49. Calne RY, Sells RA, Pena JR, et al. Induc-tion of immunological tolerance by porcine liver grafts. Nature 1969; 223:472.
50. Davies DR, Pollard SG, Calne RY. Forum on immune suppression: Hellenic Transplantation Society. Athens, Greece, 1 990.
|
|
