World J. Surg.24, 834-843, 2000 DOl: 10.1007/5002680010134 WORLD Journal of SURGERY © .lOOO by rhe Societe Internationale J(" Ch!wrgie Historic Landmarks in Clinical Transplantation: Conclusions from the Consensus Conference at the University of California, Los Angeles Carl G. Groth, M.D., Ph.D.,l Leslie B. Brent, B.Sc., Ph.D} Roy Y. Caine, M.D} Jean B. Dausset, M.D., Ph.D.,4 Robert A. Good, M.D., Ph.D.,s Joseph E. Murray, M.D.,6 Norman E. Shumway, M.D., Ph.D} Robert S. Schwartz, M.D} Thomas E. Starzl, M.D., Ph.D} Paul I. Terasaki, Ph.D.,l° E. Donnall Thomas, M.D}l Jon J. van Rood, M.D., Ph.DY 1Department of Transplantation Surgery, Karolinska Institute, Huddinge Hospital, SE-141 86 Huddinge, Sweden 230 Hugo Road, Tufnell Park, London N19 5EU, UK 'Department of Surgery, University of Cambridge, Douglas House Annexe, 18 Trumpington Road, Cambridge CB2 ZAH, UK "Foundation Jean Dausset-C.E.P.H., 27 rue Juliette Dodu, 75010 Paris Cedex, France 5Department of Pediatrics, Division of Allergy and Immunology, All Children's Hospital, 801 Sixth Street South, SI. Petersburg, Florida 33701, USA "Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA 'Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305-5247, USA 'The New England Journal of Medicine, 10 Shattuck Street, Boston, Massachusetts 02115-6094, USA 9Department of Surgery, University of Pittsburgh, School of Medicine, Thomas E. Starzl Transplantation Institute, 3601 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA 1012835 Parkyns Street, Los Angeles, California 90049, USA lIDepartment of Medicine, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024, Seattle, Washington 98109-1024, USA 12Department of Immunohematology and Blood Bank, University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands Abstract. The transplantation of organs, cells, and tissues has burgeoned tions about their own unique contributions. The ultimate objec­ during the last quarter century, with the development of multiple new tive, however, was to reach a consensus by the group on what were specialty fields. However, the basic principles that made this possible were established over a three-decade period, beginning during World War the most critical historical discoveries that made transplantation a II and ending in 1974. At the historical consensus conference held at form of clinical therapy. Carl G. Groth (Stockholm) was invited to UCLA in March 1999, 11 early workers in the basic science or clinical be the Chairman for these consensus deliberations and to prepare practice of transplantation (or both) reacbed agreement on tbe most the executive summary. significant contrihutions of tbis era tbat ultimately made transplantation the robust clinical disc;ipline it is today. These discoveries and achieve­ Historical landmark status was restricted to contributions made ments are summarized here in six tables and annotated witb references. at least a quarter of a century ago.· By this time it had been established that rejection of organ allografts could be prevented or reversed with immunosuppressive drugs and that variable do­ The symposium making up this issue of the Journal was held at the nor-specific immunologic tolerance of the graft subsequently de­ University of California, Los Angeles (UCLA) and announced by veloped in many patients. Long-term survival of human recipients the Department of Surgery hosts as "a unique and historic meet­ of organ and bone marrow allografts had been repeatedly ob­ ing at which pioneers of transplantation from around the world tained, ensuring continuation of such clinical efforts. A large will present and discuss landmarks in the advancement of trans­ number of HLA antigens had been discovered, allowing efforts at plantation biology." The participants (in alphabetical order) were: tissue matching to proceed. The scientific articles annotating this Leslie B. Brent (London), Roy Y. Caine (Cambridge, UK), Jean progress are listed in six tables under the following headings: Dausset (Paris), Robert A. Good (St. Petersburg, FL), Joseph E. transplantation immunology, bone marrow transplantation, renal Murray (Boston), Norman E. Shumway (Palo Alto), Robert S. transplantation, liver transplantation, heart transplantation, and Schwartz (Boston), Thomas E. Starzl (Pittsburgh), Paul I. Ter­ tissue matching. The material presented in these tables, including asaki (Los Angeles), E. Donnall Thomas (Seattle), Jon J. van the citations, originated from the participants of the symposium. Rood (Leiden). It should be noted that transplantation could not have pro­ Each of these 11 pioneers provided for publication their reflec- ceeded without contemporaneous advances in general and tho­ racic surgery, medicine, and anesthesia, such ;:tS open-heart sur­ Correspondence to: CG. Groth, M.D., Ph.D. gery, renal dialysis, antibiotics, and intensive care technology. The Groth et aI.: Consensus Conference 835 Table 1. Transplantation immunology. Author Discovery or application Year published Reference Gibson Defined the immunologic nature of skin allograft rejection in humans, 1943 confirmed subsequently with controlled rabbit experiments. Owen Discovered that bovine dizygotic twins with placental vascular anastomoses 1945 2 (freemartin cattle) were red blood cell chimeras. Burnet Based on Owen's observations and on studies of lymphocytic 1949 choriomeningitis virus by Traub, Burnet, and Fenner postulated "the development of tolerance ... during embryonic life." Anderson Demonstrated mutual tolerance to skin grafts by freemartin cattle twins and 1951 4 speculated that "actively acquired tolerance" was responsible. Billingham Produced actively acquired donor specific tolerance to skin allografts in mice 1953 5 injected during late fetal life with donor hematolymphopoietic cells. Simonsen Independently demonstrated GVHD in chick embryos (manifested as 1957 Billingham pancytopenia) and mice (runt disease) after intravenous injection of adult 1957 spleen cells. Starzl Reported evidence that human kidney allografts under azathioprine­ 1963 prednisone induced variable donor specific nonreactivity. GVHD: graft-versus-host disease. cardiopulmonary resuscitation procedures introduced during the the mechanistic linkage of engraftment after these two kinds of 1950s were particularly influential because they mandated redef­ transplantation was established with the discovery of donor leu­ inition of death in terms of irreversible brain damage rather than kocyte micro chimerism in long-surviving human organ recipients. the cessation of heartbeat and respiration. While salvaging count­ The clonal selection theory proposed in 1949 by Burnet and less victims of cardiac or pulmonary arrest, the new methods also Fenner marked the beginning of a new wave in immunology, from resulted in brain-dead corpses on physiologic life support. which transplantation is often viewed as a mere stream. Instead, In 1966, at a symposium on medical ethics in London, G.P.I. transplantation is a mighty tributary. It fostered research into the Alexandre described the criteria of brain death that had been used mechanisms of the destructive antigraft immune response and the in Belgium and France for discontinuing mechanical ventilation of control of this response. From these efforts, directly or indirectly, "heart-beating cadavers." It became possible thereby to remove came the discovery of the function of the lymphocyte (1959-1961) kidneys and other organs from cadaver donors with an intact and the role of the thymus in the ontogeny of the immune system circulation. The concept was further eI3.borated in a Harvard­ (1961); delineation (1958-1963) of the human major histocom­ based ad hoc committee report in 1968 in the Journal of the patibility complex (MHC); distinction of the T and B lymphocyte American Medical Association. The impact on transplantation of subsets (1967-1968); and mainly by study of antiviral immune cadaver organs was immediate and lasting. responses, demonstration of the MHC-restricted nature of the adaptive immune response (1968-1974). Transplantation Immunology The modern age of transplantation immunology (Table 1) [1-8] Bone Marrow Transplantation began·with three seminal observations. First, rejection is a host­ versus-graft (HVG) immune reaction. Second, a similar immune Bone marrow transplantation (Table 2) [9-22J had its roots in reaction [graft -versus-host (GVH) 1may occur in reverse and lead radiobiology and hematology, and it was influenced by clinical to lethal graft-versus-host disease (GVHD). Third, it is possible studies of certain inherited immune deficiency diseases. Early in under well defined experimental conditions to avert rejection as these efforts it was learned that engraftment of histoincompatible well as GVHD and to induce tolerance of alloantigens, which is bone marrow can cause lethal GVHD in a recipient rendered strongly associated with the persistence in the recipient of donor immunologically defenseless by cytoablation, a complication also leukocyte chimerism. predicted in recipients with immune deficiency disease. Conse­ The next step was the recognition that organ allografts are quently, the preclinical and clinical development of bone marrow inherently tolerogenic, a property without which their transplan­ transplantation was delayed until reliable methods of HLA typing tation with long survival