--------------_.. -- TRANSPLANTATION REVIEWS VOL 7, NO 2 APRIL 1993 The French Heritage in Clinical Kidney Transplantation 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 allotransplantation.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 graft 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 bone marrow 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