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TRANSPLANTATION REVIEWS VOL 7, NO 2 APRIL 1993 The French Heritage in Clinical Thomas E. Star;d

he different starting points and uneven empha­ twin transplantations performed by Murray (Nobel T sis of historical accounts of transplantationl laureate 1990) and his associatesll in Boston. have tended to obscure the contributions to this field Visitors flocked to France in the early 1950s to of some of the grand figures of French medicine and learn first hand from this experience, including John science. Clinical transplantation activity began in Merrill of Boston, as Hume described in the classical France within the first few years of the 20th century, account of his own clinical trials at the Peter Bent when Jaboulay in Lyon2 and other investigators in Brigham Hospital. 12 The extensive discussion of the France and Germany performed subhuman primate French experience by Hume was typical of this man to human kidney heterotransplantationY; In 1936, whose awareness and acknowledgment of other peo­ the Russian Yu Yu Voronoy of Kiev made the first ple's work was noteworthy throughout his illustrious known attempt at renal .6 career. As important as these and later contributions The field of transplantation lay largely dormant ofKussll and Hamburgerl4 were, the scientific basis until 1951 when Rene Kussl and Charles DubostG of for transplantation in France went far deeper. The Paris and Marceau Servelle of Strasbourg9 per­ roots of histocompatibility research were nourished formed a series of cadaveric renal transplantations. in France by Jean Dausset (Nobel Laureate 1980),15 The kidneys were removed from comict donors after In addition, George i\Iathe, the father of cell trans­ their execution by guillotine. The next year, French plantation, was part of the Paris clique of the 1950s physician Jean Hamburger, working with urologist and early 1960s. Louis Michon at the Hopital Necker (Paris) reported The skills necessary to transplant the kidney (the the now commonplace transplantation of a kidney only candidate organ until the 1960s) were applica­ from a live volunteer donor. 1O The pelvic kidney tions of what were becoming conventional surgical transplant procedure originally used by Kuss and practices after World War II, The vascular surgical refined subsequently by the French surgeons has technology came from the Frenchman Alexis Car­ been used hundreds of thousands of times since then reljI(i and had a pervasive effect on essentially all including for the celebrated identical (monozygotic) surgical specialties, Although Carrell understood that transplanted organs were not permanently ac­ cepted, the biological specificity of the field of trans­ From the Pittsburgh Transplant Institute and the Department if plantation was defined by Medawar when he showed Surgery, Ullivmity ifPittsburgh Health Science Center, Pittsburgh, PA. that rejection is an immunologic evenL l7,IH In retro­ Supported b)' Project Grant A,). DK 29961ftom the National Institutes spect, every further development was a logical and ojHealth, Bethesda, .VID. Presented at the Uemes foumees de Chirurgie, University of Rellne,l, inevitable step from this beginning. If rejection was Remus, France, (April 2. 1992). Published with minor differences in in fact an immune reaction, what could be more Perspectives in Biology and Medicine, 1993. logical than to protect the organ transplant by Address reprint requests to Thomas F. Star;:,!. MD, PhD, Department of weakening the immune system? Medawar's conclu­ SU~t;ery. 3601 Fiji)' Ave, 5C Folk Clinic. Unllmit)' if PittsbuZ!!,h, sion about the nature of rejection was strengthened Piltsbu~l!,h, PA, 152l3. Copyright © 1993 by WE. Saunders Company when it was shown more than 40 years ago that 0955-170Xj 93/0702-0001 $5,00/0 adrenal corticosteroids19,20 and total body irradia-

Tramplantation Revieu'J. Vol 7, No 2 (A/llil), 1993:pp 65-71 65 66 Thomas E. Star:d

tion/ I which already were known to diminish immu­ Their efforts were successful. vVhen the results of nologic responses, significantly prolonged skin Main and Prehn were confirmed by Trentin,2B the sun'ival. prototype strategy for induction of tolerance in large The relatively modest delay of rejection of rodent animals and in humans seemed at first to be obvious. skin grafts made possible with corticosteroids and Bad news was close behind. Within a few months, it total body irradiation was not an open imitation for became clear that GVHD similar to that in the clinical application.l\"or was there a clinical mandatc perinatal mouse model could be expected almost in the 1953 articlc by Billingham et aj22 that de­ invariably after all engraftments that scribed permanent skin graft acceptance in a special "took" following irradiation, except thosc from per­ circumstance not invoh'ing iatrogenic immunosup­ fectly histocompatible donors. pression. The unique circumstance was the inocula­ Although the bubble had burst, Mannick, Lochte, tion of fetal or perinatal mice ,dth immunocompe­ Ashley, Thomas, and Fcrrebee at Cooperstown, l\"'Y tent spleen cells. Instead of being rejected, these cclls (an affiliate of Columbia University), produced bone survived and endowed the recipient with the ability in marrow chimerism in 1958 in an irradiated beagle later life to accept other allogeneic tissues (in their dog, followed by successful kidney allotransplanta­ experiments skin) from the original donor strain.22 ,2) tion from the original marrow donor. 29 The animal As Billingham, Brent, and Medawar (later re­ lived for 73 days before dying from pneumonitis and ferred to as the "holy trinity") meticulously anno­ was the first "successful" marrow-kidney chimera in tatcd, the impetus and rationale for these experi­ a large animal. However, efforts by Humc et apo and ments came originally from the observation by Owen24 others to extend the Main-Prehn irradiation plus that freemartin cattle (the calf equivalents of human bone marrow technology to mongrel dog kidney fraternal t\\ins) were permanent hematopoietic chi­ transplantat ion was totally unsuccessfullv. Later, in meras if placental fusion and fetal cross-circulation summarizing his many years of collaborative re­ had existed in utero. Burnet and Fenner25 predicted search with the Cooperstown group, Rapaport con­ that such chimerism and thc ability to exchange firmed that this strategy could not work in dogs other tissues could be induced by the kind of experi­ unless perfectly tissue-matched marrow donors were ment eventually performed with Medawar by Billing­ used-usually litter mates.3! Under all other condi­ ham and Brent whosc definition of tolerance was tions, lethal GVHD, rejcction, or both were to be that it "is due to a primary central failure of the expccted. Appreciation of this dilemma by the clini­ mechanism of the immunological reaction, and not cians caused a break in ranks in the late 1950s to some intercession, at a peripherallevel."23 between those interested in bone marrow transplan­ The surgical interest generated by thc dcmonstra­ tation for the treatment of hematologic disordcrs tion that tolerance could be acquired was quickly and those to whom the bone marrow was only the dampened whcn it was learned by Billingham and means to the end of transplantation of a needed solid Brent26 with further experiments in mice that the organ of which the kidney was the sole candidate at penalty for the prophylactic infusion of such donor the time. cells could be lethal graft-versus-host disease From this point onward, the therapeutic philoso­ (GVHD). Many of the inoculated mice failed to phies of bone marrow and solid organ transplanta­ thrive ("runt disease") and had skin erosions, hair tion took separate pathways--one dependent and loss, diarrhea, diffuse pneumonitis, and characteris­ the other seemingly independent of classical toler­ tic changes in their lymphoid organs. Donor immune ancc induction. In spitc of the consequent donor pool cells were found everywhere in the recipient tissues. limitations (essentially only perfectly matched sib­ The objective of producing specific and stable lings being permissible), bonc marrow transplanta­ allogeneic (often called ~Iedawarian) nonresponsive­ tion, which was first accomplished clinically in 1968 ness became the holy grail of transplantation when in by Robert Good of the Univcrsity of Minnesota32 and 1955, Main and Prehn27 simulated in adult mice an soon thereafter by Thomas (Nobel Laureate 1990)33 environment lhat they likened to that in perinatal and yan Bekkum,34 matured into accepted clinical Billingham-Brent-Medawar animals. The three steps therapy for hematologic diseases and an assortment were first, to cripplc the immune system with supra­ of other indications. lethal total body irradiation, ncxt to rescue it with In contrast, solid organ transplant surgeons were allogeneic bone marrow (creating a chimera), and quick to abandon effort to produce specific allogeneic finally to engraft skin from the bone marrow donor. unresponsiveness with bone marrow. In Boston, Mur- French Heritage in Kidney Transplantation 67 ray and Merrill35 used the Main-Prehn principle of had achieved to variable degrees the kind of graft recipient preparation in their first two attempts at acceptance that later was seen in tens of thousands of human kidney allotransplantation in 1958, but elimi­ drug-treated humans after all kinds of whole organ nated the bone marrow component for the next 10 transplantation. The fact that the mechanism was recipients, using sublethal total body irradiation the same has been appreciated only in the last few alone.35,36 Although 11 of their 12 irradiated recipi­ months when it was realized that extensive migra­ ents died after 0 to 28 days, the survivor, the recipient tion and repopulation of sessile tissue leukocytes of a fraternal twin kidney inJanuary 1959, lived until (most obviously of dendritic cells) from graft to host 1979 and was the first example of a successful and vice versa are events common to the "acceptance" transplantation beyond the identical twin.35.37 of all solid organs using any immunosuppressive Five months later, Hamburger et aI'4,38,39 added a modality-creating chimerism in the graft but also second successful fraternal (dizygotic) twin case. This systemically in the recipient.43 \'\!hat has been achieved patient had good renal function until his death 26 with drugs and antilymphoid agents compared with years later from carcinoma of the urinary bladder. sublethal irradiation is a greater ease and reliability However, in the Boston and Paris fraternal twin of achieving this transition. recipients, the possibility remained that their individ­ In view of the historic developments through ual placentas had cross-circulated with those of their 1960, it was not surprising that the search for kidney donors, like the conditions in Owen's freemar­ immunosuppressive drugs was focused at first on tin cattle. This possibility was precluded in the myelotoxic agents that were viewed as "space mak­ further extraordinary kidney transplant experience ers" for new donor or recovering recipient bone in France during 1960 and 1961 using total body marrow, and thus the pharmacologic equivalent of irradiation without bone marrow reconstitution. total body irradiation. Willard Goodwin of Los Ange­ Hamburger et al 14,39 succeeded with kidney transplan­ les achieved sublethal bone marrow "burn out" with tation from a sibling and a first cousin. The cousin methotrexate and cyclosphamide in a living related­ kidney functioned for 18 years before retransplanta­ kidney recipient in September 1960, who subse­ tion was performed without interim dialysis in a quently developed rejection that was reversed with patient who now is a member of the French parlia­ prednisone. This was the first example of protracted ment and the longest surviving kidney allograft human kidney graft survival (143 days) with drug recipient (32 years) from that heroic and primitive treatment alone.44 era.4() Kidney transplant surgeons were quick to appreci­ Also in Paris, Rene Kuss had long-term survival of ate that myelotoxicity should be avoided, not deliber­ three of six irradiated patients treated with kidney atey imposed. The most important step in this transplantation fromJ anuary 1960 through 1961. 13,41 evolution was the discovery by Schwartz and Dame­ This was a truly extraordinary achievement because schek that 6-mercaptopurine was immunosuppres­ two of Kuss's long surviving patients were given sive without bone marrow depression in nontrans­ nonrelated kidneys (the first in June 1960) that plant models.45 Within a few months, Schwartz and functioned for 17 and 18 months. During the critical Dameschek46 and Meeker (working with Good)47 period of 1959 through early 1962, the cumulative showed that this drug could mitigate skin graft French experience was the principal (and perhaps rejection in rats. Close behind, Calne48 and Zukos­ the only) justification to continue clinical kidney ki49 demonstrated independently of each other that transplantation trials.42 By showing that bone mar­ kidney rejection in dogs also was ameliorated. row infusion was not a necessary condition for substan­ \'\!hat was achieved in the earliest kidney trans­ tial prolongation of kidney grafts, the stage was set plant experiments using drugs was delay of the for the transition to drug therapy. In fact, Kuss was inevitable rejection or else death of the animal from using 6-mercaptopurine and steroids as adjuvant over immunosuppression. However, occasional exam­ therapy in his patients as early as 1960. 13 ples of long-term or seemingly permanent allograft Those examining this period historically have acceptance were observed throughout 1962 and been inclined to consider irradiation-induced and 19635()'53--defined as long survival of transplanted drug-induced graft acceptance as different phenome­ mongrel kidneys after a 4- to l2-month course of na.4,36,37 However, it seems certain that the Boston 6-mercaptopurine or azathioprine was stopped. Since and Paris fraternal twin kidney recipients, as well as then, each new major immunosuppressive agent (or the five long-surviving nontwin French recipients, drug cocktail regimen), including cyclosporine and 68 Thomas E. Starz;l

FK506, has generated excited claims of the same At 12 months, the blood urea nitrogen in this patient phenomenon. Throughout the years, the most po­ was 100 mg%. The allograft failed between 18 and 24 tent agcnts for induction of this state have been the months, and thc patient died at 27 months. However, antilymphoid sera and globulins that at the begin­ this pioneer recipient was the first to achieve long ning were polyclonal agents54,55-but later highly survival with azathioprine, and thus he was an specific monoclonal preparations.56 Although vari­ opening wedge into a new era. able in its incidence, the graft acccptance observed In Colorado, where the synergism of azathioprine with all these modalities was indistinguishable and and prednisone was known from the animal work, thus was not a treatment-specific phenomenon. these two drugs were used together from the outset This new kind of graft acceptance in outbred dogs with results that exceeded everyone's expect a­ was easier to produce with drugs than with total body tionslil ,1i2 and precipitated a revolution in clinical irradiation, but the number of absolute examples transplantation. Success hinged on the fact that was (and is) cxtremely small in contrast to what can acute rejection usually could be reversed with predni­ be achieved todav in small rodents. In summarizing sone as had been shown in our dogs under baseline his research v~ith Caine, Alexandre, Sheil, and other therapy with azathioprine57 and as Goodwin had investigators using azathioprinc,") Murray described observed in a kidney recipient whose primary treat­ a 20-day mortality of approximately 50% and a ment had been with methotrexate and cyclophospha­ 3-mon th mortality of 90% in a series of 120 mongrel mide.44 Both Hamburgerl4 and KuSS l3 had adminis­ dogs given daily treatment. Eventually a handful of tered steroids to their irradiated patients although long-survi\ ing animals « 5%) was the distillation no details were given. In a lapse of scholarship in our from I ,000 experiments with 6-mercaptopurine or 1963 article,') 1 we failed to acknowledge the French azathioprine performed in Boston by .\1urray's team use of steroids or the earlier experimental work of in work that was initiated with the arrival there of Sir Billingham et a]l9 and the American, Morgan.2o Roy Caine inJune 1960:)2 Although these oversights were corrected in our The animals proudly displayed as chronic survi­ experimental report,57 we already had unwittingly vors in laboratories of Boston, Denver, Richmond, distorted all subsequent literature on this subject. and Minneapolis were those precious few who had The second and far more fundamental observa­ run the gauntlet of therapy to the point where tion in these patients was that the amount of drug treatment was stopped. Our results in Colorado treatment required to prevent rejection often be­ were similar to those in Boston but with one striking came less in time,61 allmving the lifetime rehabilita­ difference. Adrenocortical steroids were shown to tion of some of the patients. Of the first 64 patients reverse rejection in 88% of our dogs, sometimes in in the Colorado series compiled between 1962 and spectacular fashion, before the steroids almost al­ \larch 1964,62 15 survived for the next 25 years. Two ways caused fatal peptic erosions of the gastrointesti­ stopped all immunosuppression ,~thout rejection for nal tractY 25 and 27 years, thus mimicking completely the It was on this dismal record that the clinical phenomenon occasionally observed in dogs and in kidney transplant trials of the early 1960s were the irradiated Boston and Paris fraternal twins. 0J'ine based. In a display of optimism that would not be other patients from the era preceding early 1964 tolerated in the clinical research climate of today, the including three treated by David Hume of Richmond rare exception was given more weight than the were still alive in six other centers in the summer of customary failure. Thus, the poor results came as no 1989.40 It was noteworthy that none of these quarter surprise when the drugs were first used for patients century su[\~vors had been given a nonrelated kid­ in the same way as had been tried in the dogs.~6,58 ney. The first such example in the world was a However, one of the Boston patient s whose transplan­ cadaver kidney recipient treated in Paris by Ham­ tation under azathioprine was in April 1962 had burger in October 1964 who passed the 25 year mark functional graft survival for more than 18 months in October 1989.40 after receiving the kidney of a patient who could not The reversibility of rejection and change in host­ be weaned from a heart-lung apparatus after open graft relationship eventually were verified with all heart surgery.58,59 Because cardiopulmonary bypass other transplanted organs, beginning with the liver. 63 was in effect, the physiologic conditions for procure­ Although immunosuppression has improved, the ment were unusually advantageous and were in fact central therapeutic dogma for solid organ transplan­ comparable to those with a "heart beatingcadaver".lio tation that had emerged by 196361 ,62 has changed French Heritage in Kidney Tramplantation 69

Table 1. Drug Cocktail Formulation that exceeded the wildest expectations of the immu­ Central Therapeutic Dogma Baseline Agents nologists. At the outset, the Peter Bent Brigham Hospital was the sole American forerunner of the Baseline therapvwith one Azathioprine new field of transplantation, soon to be joined by Will or two drugs Cyclophosphamide Goodwin's University of California at Los Angeles Secondary adjustments Cyclosporine with steroids or anti­ Cyclosporine-azathioprine program in 1960. By .January 1963, Goodwin's pro­ lymphoid agents FK506 gram had self-imposed a moratorium, but the num­ Case-to-case trial (and FK506-azathioprine ber of active clinical centers in America had grown to paten tial error) of three-the Brigham, the Medical College of Vir­ weaning ginia, and the University of Colorado. There were scarcely more in all of Europe, but by this time the very little in nt'arly 30 years. The dogma calls for two in Paris already had been in existence for more daily treatment with one or two baseline drugs with than a dozen years. At the end of 1963, the gold rush further immune modulation by the highly dose­ was on with a wild proliferation of kidney transplant maneuverable adrenal cortical steroids to whatever centers on both sides of the Atlantic. Trials with the level is required to maintain stable graft function liver, the next \ital organ beyond the kidney, had (Table I). The strategy readily incorporated the started66 and clinical heterotransplantation with antilymphoid drugs in 1966,54 and after CaIne's chimpanzee67 and baboon68 donors had been system­ introduction of cyclosporine64 the dogma again was atically tried with encouraging although ultimately found applicable.65 unsatisfactory results. A truly amazing period in the history of transplan­ These events and subsequent ones could not have tation was 1959 through 1963, which led to successes transpired in the way they did without the French

Figure 1. (Left) Rene Kuss (1913- ), approximately 1966. (Right) Jean Hamburger (1909-1992), approximately 1985. 70 ThomaJ E. Star;:.i pioneers, Hamburger the physician and Kuss the TIL"-: Ten Recollections. Los Angeles, CA, ccrA Tissue surgeon (Fig 1), and their friends in Boston whose Typing Laboratory, 1990, pp 1-19 vision was greater than that giwn to most men and 16. Carrd A: The operative techniqUE for vascular anastomoses and transplantation of visccra. Lyon :-'Ied 1902,98:859 women. Workers in the two cities founded a clinical 17. Medawar PB: The behavior and fate of skin autografts and discipline where none existed before and then per­ skin homografts in rabbits.J Anat 1944, 78: 176 sisted despite allegations of folly or worse. The 18. Meclawar PB: Second study of behavior and fate of skin French successes with kidney transplantation oyer homografts in rabbits.J Anat 1945, 79: IS 7 the three-year period from 1959 through early 1962 19. Billingham RE, Krohn PL, Medawar PB: Effects of cortisone on survival of skin homografts in rabbits. Br Med] 1951, kept the flames alive when all other efforts were I: I 157 failing. 20. :-'lorgan JA: The influence of cortisone on t he survival of homografts of skin in the rabbit. Surgery 1951,30:506 21. Dempster WJ, Lennox B, BoagJW: Prolongation of survival of References skin homotransplants in the rabbit by irradiation of the host. Br] Exp Pathol 1950,31 :670 I. Terasaki PI (ed): History of Tral)splantation: Thirty-Five 22. Billingham RE, Brent L, Medawar PB: "Actively acquired Recollections. Los Angeles, CA, UCLA Tissue Typing Labora­ tolerance" of foreign cells. Nature 1953, 172:603 tory, 1991, 1'1'1-704 23. Billingham R, Brent L, '\ledawar P: Quantitative studies on 2. ]aboulay :-'1: Greffe clu reins au pli du conde par soudures tissue transplantation immunity. III. Actively acquired toler­ arterielles et veineuses (Kidney grafts in the antecubital fossa ance. Philos Trans R Soc Lond (BioI) 1956,239:357 bv arterial and venous anastomosis). Lyon Medical 1906, 24. Owen RD: Immunogenetic consequences of vascular anasto­ 107:575 moses between bovine twins. Science 191-5,102:400 3. Unger E: i\ierentransplantation (Kidney transplantation). 25. Burnet FM, Fenner F: The Production of Antibodies (ed 2). Wien K1in Wochenschr 1910,17:573 Melbourne, Australia, Macmillan, 1949, pp 1-142 4. Groth CG: Landmarks in clinical renal transplantation. Surg 26. Billingham R. Brent 1: Quantitative studies on transplanta­ GynecolObstet 1972, 131:323 tion immunity. N. Induction of tolerance in newborn mice 5. Hau T: in Landes RE (cd): Clio Chirurgica: Renal Transplan­ and studies on the phenomenon of runt disease. Philos Trans tation. Austin, TX, Silvcrgirl, 1991, pp 1-326 R Soc Lonel (BioI) 1956,242:439 6. Voronoy Yu Yu: Sobre cl bloqueo del aparato reticuloendote­ 27. !'.Iain ]M, Prehn RT: Successful skin homografts after the lial del hombrc en algunas formas de intoxicacion por e I administration of high dosage X radiation and homologous sublimado y sobre la transplantacion del rinon cadaverico bone marrow. .I Natl Cancer Inst 1955, 15:1023 como metodo de t ratimiento de la anuria consecutiva a aquella intoxicacion (Blocking the ITticuloendothelial system 28. TrentinJJ: Mortality and skin transplantibility in X-irradiated mice recei\~ng isologous or heterologous bone marrow. Proc in rnan in sorne forms of Inercuric chloride intoxication and the transplantation of the cadaver kidney as a method of Soc Exper BioI Med 1956,92:688 treatment for the anuria resulting from this intoxication). 29. Mannick JA, Lochte HL, Ashley CA, et al: A functioning Siglo Med 1937,97:269 kidney homotransplant in the dog. Surgery 1959,46:821 7. Kuss R, TeimurierJ, MilJiez P: Quelques essais de greffer rein 30. Humc DM,] ackson BT. Zukoski CT, et al: The homotransplan­ chez l'homme. Mem Acad Chir 1951,77:755 tation of kidneys and of fetal liver and spleen after total body 8. Dubast C, Oeconomos N, Nenna A, et al: Resultats d'une irradiation. Ann Surg 1960, 152:354 tentative cle greffe rmale. Bull Soc Med Hop Paris 1951, 31. Rapaport Fr, Bachvarofr RJ, Mollen N, et al: Induction of 67: 1372 unresponsiveness to major transplantable organs in adult 9. Servelle M, SmIlie P, Rougeulle J: Greffe d'une rein de mammals.AnnSurg 1979, 190:461 supplicie a une malade m'ec rein unique congenital, atteintt 32. Good RA: Immunologic reconstitution: The achievement and de nephrite chronique hypertensive azatemique. Bull Soc Mecl ils meaning. Hosp Pract 1%9,4:41 Hop Paris 1951,67:99 33. Thomas ED: Allogeneic marrow grafting: A story of man and 10. Michon L, Hamburger .I, Oeconomos N, et al: Une tentative dog, in Terasaki PI (cd): History of Transplantation: Thirty­ de transplantation renalc chez I'homme. Aspects NIedicaux et Fiv'c Recollections. Los Angeles, CA, UCLA Tissue Typing Biologiques. Presse Med 1953,61: 1419 LaboratOI'\. 1991, pp 379-')93 II. Merrill JP, MurrayJE, Harrison JH, et al: Successful homo­ 34. van Bekkum DW: Bone marrow transplantation: A story of transplantation of the human kidney between identical twins. stem cells, in Terasaki PI (cd): History of Transplantation: ]AMA 1956,160:277 Thirty-Five Recollections. Los Angeles, CA, GCLA Tissue 12. Hume DM, :'vlcrrill]P, :-'Iiller BF, et al: Experience with renal Typing Laboratory, 1991, pp 395-434 homotransplantation in the human: Report of nine cases. J 35. MurrayJE, Merrill]P, Dammin GJ, et al: Study of transplan­ Clin Invest 1955, 34:327 tation immunity after total body irradiation: Clinical and 13. Kuss R, Legrain M, :\lathe G, ct al: Homologous human experimen tal investigation. Surgery 1960,48:272 kidney transplantation. Experience with six patients. Postgrad 36. Murray]E, Mcrrill]P, Dammin GJ, ct al: Kidney t ransplanta­ Med] 1962,38:528 tion in modified recipients. Ann Surg 1962,156:337 14. HamburgerJ, VaysseJ, Crosnier], et al: Renal homotransplan­ 37. MurrayJE: Nobel Prize Lecture: The first successful organ tation in man after radiation of the recipient. AmJ Mcd 1962, transplants in man, in Terasaki PI (cd): History of Transplan­ 32:8.'i4 tation: Thirty-Five Recollections. Los Angeles, CA, UeL". 15. Dausset]: The HLAadventurc, in Terasaki PI (ed): History of Tissue Typing Laboratory, 1991, pp 121-143 French Heritage in Kidney Transplantation 71

38. HamburgcrJ, VaysseJ, CrosnierJ, et al: Transplantation of a 54. Starzl TE, Marchioro TL, Porter KA, et al: The use of kidney between nonmonozygotic twins after irradiation of the heterologous antilymphoid agents in canine renal and liver receiver. Good function at the fourth month. Pre sse Med homotransplantation and in human renal homotransplanta­ I 95Cl, 67:1771 tion. Surg Gynecol Obstet 1967, 124:301 39. Hamburger J: :\1cmories of old times, in Terasaki PI (ed): 55. Scanfield I, WolfJS, Wren SF, et al: Mechanism of permanent History of Transplantation: Thirty-Five Recollections. Los survival of canine renal allografts follo"lng a limited course of Angeles, CA, UCLA Tissue Typing Laboratory, 1991, pp 61-71 ALS treatment. Transplant Proc 1973,5:533 40. Starzl TE, Schroter GPJ, Hartmann NJ, et al: Long-term (25 56. Cosimi AB, Burton RC, Colvin RB, et al: Treatment of acute year) survival after renal homotransplantation-The world renal allograft rejection with OKT3 monoclonal antibody. experience. Transplant Proc 1990,22:2361 Transplantation 1981,32:535 41. Kuss R: Human renal transplantation memories, 1951 to 1981, in Terasaki PI (ed): History of Transplantation: Thirty­ 57. Marchioro TL, Axtell HK, LaVia MF, et al: The role of Five Recollections. Los Angeles, CA, UCLA Tissue Typing adrenocortical steroids in reversing established homograft Laboratory, 1991, pp 37-59 rejection. Surgery 1964,55:412 42. Starzl TE: My thirty-five year view of , in 58. MurrayJE, MerrillJP, HarrisonJH, et al: Prolonged survival Terasaki PI (ed): History of Transplantation: Thirty-Five of human-kidney homografts by Recollections. Los Angeles, CA, UCLA Tissue Typing Labora­ therapy.NEnglJMed 1%3,268:1315 tory, 1991, pp 145,181 59. Murray JE, Wilson RE, O'Connor l\'E: Evaluation of long­ 43. Starzl TE, Demetris AJ, Murase N, et al: Cell migration, functioning human kidney transplants. Surg Gynecol Obstet chimerism, and graft acceptance. Lancet 1992,339:1579 1967, 124:509 44. Goodwin WE, Kaufman lJ, Mims MM, et al: Human renal 60. MerrillJP, MurrayJE, Takacs F: Successful transplantation of transplantation. I. Clinical experience with six cases of renal kidney from a human cadaver.JAMA 1963, 185:347 homotransplantation.J Uro11963, 89: 13 61. Starzl TE, Marchioro TL, Waddell WR: The reversal of 45. Schwartz R, Dameshek W: Drug-induced immunological rejection in human renal homografts with subsequent develop­ tolerance. Nature 1959, 183: 1682 ment of homograft tolerance. Surg Gynecol Obstct 1963, 46. Schwartz R, Dameshek W: The effects of 6-mercaptopurine on homograft reactions.J Clin Invest 1960,39:952 117:385 47. Meeker W, Condie R, Weiner D, ct al: Prolongation of skin 62. Starzl TE: Experience in Renal Transplantation. Philadelphia, homograft survival in rabbits by 6-mercaptopurine. Proc Soc PA, Saunders, 1964, pp 1-383 Exp BioI Med 1959, 102:459 63. Starzl TE: Experience in Hepatic Transplantation. Philadel­ 48. CaIne RY: The rejection of renal homografts: Inhibition in phia, PA, Saunders, 1969, pp 1-545 dogs by 6-mercaptopurine. Lancet 1960, 1:417 64. CaIne RY, Rolles K, White DJG, et al: Cyclosporin A initially 49. Zukoski CF, Lee HM, Hume DM: The prolongation of as the only immunosuppressant in 34 recipients of cadaveric functional survival of canine renal homografts by 6-mercapto­ organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979, purine. Surg Forum 1960, 11:470 2:1033 50. Pierce JC, Varco RL: Effects of long term 6-mercaptopurine 65. Starzl TE, Weil III R, Iwatsuki S, et al: The use ofcyclosporin A treatment upon kidney homotransplants in dogs. Surgery and prednisone in cadaver kidney transplantation. Surg Gyne­ 1968,54: 1254 colObstet 1980, 151:17 51. Zukowski CF, Callaway JM: Adult tolerance induced by 66. Starzl TE, Marchioro TL, Von Kaulla KN, et al: Homotrans­ 6-mcthyl mercaptopurine to canine renal homografts. Nature 1963,198:706 plantation of the liver in humans. Surg Gynecol Obstet 1963, 52. '\furray JE, Sheil AGR, Moseley R, et al: Analysis of mecha­ 117:659 nism of immunosuppressive drugs in renal homotransplanta­ 67. Reemstma K, McCracken BH, Schlegel JU, et al: Renal tion. Ann Surg 1964. 160:449 heterotransplantation in man. Ann Surg 1964, 160:3H4 53. Starzl TE: Host-graft adaptation, in Experience in Renal 68. Starzl TE, Marchioro TL, Peters GN, et al: Renal heterotrans­ Transplantation. Philadelphia, PA, Saunders, 1964, pp 164- plantation from baboon to man: Experience with 6 cases. 170 Transplantation 1964,2:752