The Biologists

The bombing of cities during the war caused a marked increase in the number of burn victims for whom a skin autograft was not feasible. The application of skin homografts (a old term for allograft) was known for its high failure rate due to rejection. The 'War Wounds Committee' of the British Medical Council assigned a young, Oxford-educated zoologist named Peter Medawar to investigate the problem of homograft rejection and how to circumvent it. Medawar worked first in a clinical setting with Thomas Gibson at the Burn Unit at Glasgow Infirmary. In 1943, they published a detailed report "The Fate of Skin Homografts in Man" on a single burn victim with multiple 'pinch grafts' of skin. Their comprehensive analysis of serial biopsies led to the following conclusions:

l         Autografts succeed, but allografts fail after an initial take

2         "Second-set" grafts undergo accelerated rejection.

3         The breakdown of foreign skin epithelium is not due to "a local reaction" (a term used by Loeb) on the part of lymphocytes or other mesenchyme cells.

4         The destruction of the foreign epidermis is brought about by a mechanism of active immunization

This report shows the Medawar's awareness of the immunity hypotheses of Schöne, Holman, Woglom, and others to explain graft rejection. He returned to Oxford University to study the homograft rejection in laboratory animals and to prove that this was an immunologic phenomenon. A series of carefully designed and stringently controlled experiments with a rabbit skin graft model were described in two reports to the War Wounds Committee published in the Journal of Anatomy in 1944 and 1945.

Medawar concluded that the mechanism by which foreign skin is eliminated belongs to the category of actively acquired immune reactions. His early insight into the mechanism of transplant rejection is reflected by statements such as "The accelerated regression of second-set homografts argues for the existence of a systemic immune state". "The inflammation has in all likelihood the character of a local anaphylaxis" (he implicates humoral immune responses), but "yet, the reaction is atypical; for the lymphocyte takes the place of the polymorph in the 'classical picture'". He postulated that the graft-infiltrating cells are "directly concerned in the manufacture of antibodies", and that "The homograft reaction is governed by the operation of at least 7 antigens freely combined". In those days, the immunological community was almost solely focused on the humoral immune response, although some investigators, notably Merrill Chase (and Landsteiner) had obtained evidence that cutaneous hypersensitivity to picryl chloride and tuberculin could be transferred by lymphoid cells and not by antibodies.

Cellular Immune Basis of Transplant Immunity

Medawar recognized the significance of donor leukocytes in inducing transplant immunity and accelerated rejection of skin grafts. Burnet and Fenner pointed out in 1949, the analogy between transplantation immunity and delayed-type hypersensitivity, a immune response type exemplified by the tuberculin reaction. Both phenomena showed the absence of detectable antibodies, and the systemic nature of the sensitization process induced by intradermal immunization with leukocytes. A few years later, Mitchison (1954) showed that passive transfer of lymphoid cells from sensitized donors induced immunity to transplanted allogeneic tumors. Soon afterwards, Billingham, Sprent and Medawar conducted similar studies on the adoptive transfer (a term coined by Medawar) with lymph node cells in a skin allograft model and their findings firmly established a cellular basis of transplant immunity. The functional role of lymphocytes remained a mystery until at least ten years later. Most investigators considered the lymphocyte an unimportant cell which with its paucity of cytoplasm, could not have any significant functional activity. Apart form the non-immunologic functions considered by some investigators, others thought that lymphocytes were hematopoietic stem cells.Chase and others interpreted their findings that lymphocytes were involved with antibody formation although the actual production of antibodies was never established.

Gowans provided the first major step towards the understanding of lymphocytes. He demonstrated with radiolabeled thoracic duct cells, that lymphocytes recirculate from blood to lymph by crossing the endothelial walls of specialized blood vessels known as post-capillary venules. Medawar had begun to focus his efforts on the concept that lymphocytes were "immunologically competent" cells. Paul Terasaki then a post-doctoral fellow with Medawar, demonstrated that injection of small lymphocytes into newly hatched chicks induced graft-versus-host (GVH) reactions. Morton Simonsen in Copenhagen has been credited as the discover of GVH disease caused by inoculation of adult lymphoid cells in the chick embryo and manifested by severe hemolytic anemia, splenomegaly and soon death. The powerful GVH effects of allogeneic lymphocytes were also noted by Billingham and Brent in neonatal mice who developed "runt disease" and in other experimental models such as "parabiosis intoxication" in parabiotically attached animals , "secondary disease" in irradiated mice injected with allogeneic bone marrow cells (Trentin) and "F1 hybrid disease" in F1 hybrids given parental lymphocytes (Gowans).Although it was generally believed that time that lymphocytes participated in the allograft response as carriers "cell-bound" antibody, several investigators began to elucidate the functional roles of these cells in transplant immunity. During the late fifties, Govaerts in Belgium demonstrated that lymphocytes taken from dogs with rejected kidney allografts had a specific cytotoxic effect on renal cells from the donor. Rosenau and Moon showed a similar in vitro cytotoxic effect of sensitized mouse lymphocytes and it required a close contact with the allogeneic targets. Wilson in Philadelphia introduced the "single-hit" mechanism of cytotoxicity and in quantitative inhibition assays with a 6-mercaptopurine derivative, he showed that the cytotoxic effect of sensitized lymphocytes required RNA-dependent protein synthesis. During the sixties, Ginsburg in Israel applied time-lapse cinematography to show the movements of large lymphoblasts (called lysocytes) from one target to another on a cultured cell monolayer. Shortly afterwards. Brunner and Cerrottini in Switzerland developed the classical cell-mediated lympholysis (CML) assay that has been used in so many studies to increase our understanding of cytotoxic lymphocytes. For example, this assay was used in 1974 by Zinkernagel and Doherty to elucidate the role of the major histocompatibility complex (MHC) restricted nature of T lymphocyte cytotoxicity against virus-infected cells.

The Mixed Lymphocyte Culture (MLC) assay became another important tool for studying lymphocytes. Bain, Vas and Lowenstein in Montreal reported in 1963 the transformation of large immature basophilic cells from lymphocytes cultured together from two unrelated individuals. Such cells can synthesize DNA and undergo mitosis. These investigators coined the term Mixed Leukocyte Reaction (MLR) and they suggested that this reaction might be related to homograft immunity and that this test seems useful as an indicator of compatibility between siblings. Around the same time, Bach an Hirschhorn in New York developed the one-way MLC assay whereby recipient cells were studied for their response to mitomycin C-treated cells from the donor. These responses were measured after seven days by microscopic examination of fixed smears for blast cell transformation and mitosis. Bach provided first evidence for the role of histocompatibility antigens and he suggested that the MLC might be a useful typing test for transplantation. This led to an active research endeavor that resulted in the definition of the so-called lymphocyte defined histocompatibility antigens during the seventies. For many years, MLC has been used as a critical test to determine donor-recipient compatibility in bone marrow transplantation. Hayry and Defendi found that mouse lymphocytes generated from the MLR were cytotoxic to stimulator cells and Solladay and Bach reported the same phenomenon with human lymphocytes. The MLR was now considered as representing an in vitro alloactivation model of the allograft response and the CML as an in vitro model of an effector mechanism of cellular transplant immunity.

During the early sixties, independent studies by JFAP Miller in London and Robert A. Good in Minneapolis established the significance of the thymus gland in cellular immunity. Neonatal thymectomy of mice caused a severe immunodeficiency characterized by lymphopenia, a wasting syndrome and early death. Bruce Glick at the University of Wisconsin made the serendipitous discovery that early removal of the bursa Fabricius, a cloacal organ in the chicken, led to an antibody deficiency state and low levels of serum gamma globulins. These findings provided the basis to differentiate between thymus (or T)-dependent and bursa (or B)-dependent lymphocytes. Henry Claman at the University of Colorado provided crucial evidence that antibody formation required the interaction between B and T cells. These different types of lymphocytes could soon be distinguished through the expression of cell surface markers like immunoglobulins on B cells and theta markers on T cells (Reif and Allen; Raff). Furthermore, Harvey Cantor and Ed Boyse in New York identified three genetic loci Ly-1, Ly-2 and Ly-3 that could differentiate between murine cytotoxic (CD8) T lymphocytes and helper (CD4) T lymphocytes.

The "Passenger Leukocyte" concept represented another important step towards a better understanding of the allograft response. Snell noted already in 1957 from data obtained by Stork in 1953, that donor leukocytes may play a role in the induction of transplant immunity, because donor organs transplanted from cortisone treated rats had longer survivals and that such organs had reduced numbers of leukocytes. Ten years later, Steinmuller reported a series of seminal experiments whereby he first induced neonatal tolerance in mice with allogeneic hybrid spleen cells and transplanted skin from tolerant animals to syngeneic recipients. As expected, such transplants survived indefinitely but they sensitized the recipients to skin from the spleen cell donors. Steinmuller concluded that allogeneic leukocytes from the tolerizing inoculum had migrated to the skin of the tolerant mice in sufficient numbers to induce an allograft response in syngeneic recipients. He hypothesized that a "leukocyte containment" and raised the question whether the immunizing ability of skin grafts is dependent on leukocytes. The term "passenger leukocyte" was coined later by Elkins and Guttmann who in an elegant series of experiments showed that local GVH reactions could be induced by syngeneic spleen cells inoculated under the capsules of transplanted kidneys in F1 hybrid rats.

Transplantation Tolerance

Although it had become clear many years ago that the rejection problem presented a formidable barrier to successful transplantation, investigators began to wonder whether the immune system be rendered unresponsive to the transplant. Some early studies had shown the feasibility of immunological tolerance. Felton (1926) reported that high doses of pneumococcal polysaccharide can induce unresponsiveness upon rechallenge with this antigen. Landsteiner and Chase (1937) found that per os administration rather than percutaneous application of chemicals evoked unresponsiveness rather than delayed-type hypersensitivity. First evidence for transplant tolerance was however, obtained by embryologists.

During the first few decades of the twentieth century, many experimental embryologists conducted tissue differentiation studies on transplanted xenogeneic grafts in avian or amphibian embryos. These grafts were often quite successful in these hosts, but these studies never addressed any immunological implications. A notable exception is the work by Rous and Murphy who around 1912, studied the growth of rat sarcoma cells in the chorioallantoic membranes of chick embryos. These tumor cells grew quite well during the incubation period of the eggs but were rejected around the time of hatching and this was accompanied by the appearance of lymphoid cells around the graft. These data indicated for the first time a relation between the ontogeny of the immune response and graft rejection.

The discovery of neonatal transplant tolerance has been credited to Ray Owen, a geneticist at the University of Wisconsin who studied the inheritance of red blood cell antigens in cattle. He reported in 1945 that dizygotic twins had mixtures of their own cells and their twin partner cells. Thirty years earlier, Lillie had observed that bovine dizygotic twins develop a fusion of their placenta during embryonic life. This results in a common intrauterine circulation and the passage of sex hormones from the male embryo to the female twin impairs the sexual development in the female twin and the result if a sterile so-called "free-martin". Owen recognized that the common intrauterine circulation also leads to an exchange of hematopoietic stem cells during embryonic life and the establishment of the chimeric state of red cells. Moreover, these calves did not have isoantibodies to their twin partners.

A few years later, Burnet and Fenner acknowledged in their influential book "The Production of Antibodies" the importance of Owen's findings and they proposed their famous "self-nonself" hypothesis for immune development. Burnet had concluded that chick embryos and fetal animals are incapable of antibody production and that the development of immunocompetence is a slow process in young animals. He postulated that during embryonic development, "a process of self-recognition takes place" and "no antibody response should develop against the foreign cell antigen when the animal takes on independent existence". Owen's red cell chimeric model in the dizygotic cattle twins seemed similar to the phenomenon induced by inoculation of foreign embryonic cells in the chick embryo and Burnet hypothesized a "tolerance acquired by fetal exposure to 'nonself' constituents". Interestingly, two Russian scientists Lopashov and Stroyeva published independently in 1950 a paper (in Russian) reflecting similar concepts about the embryonic development of the immune response to transplants.

Medawar predicted that an exchange of skin grafts between dizygotic calves could verify Burnet's hypothesis and together with his post-doctoral fellow Rupert Billingham, he performed a series of grafting experiments that provided direct support for the concept of neonatally acquired transplant tolerance. Moreover, subsequent experiments by Billingham and Leslie Brent, then a doctoral student with Medawar, demonstrated in 1953 that neonatally acquired transplant tolerance could be achieved in mice by inoculation of embryos or intravenous injection of newborn mice with allogeneic cells. Thus, "the exposure of animals to antigens before the development of the faculty of immune response should lead to tolerance rather than to heightened resistance". It should be noted that the concept of neonatal tolerance was still solely based on antibody production, because the knowledge of cellular immunity was virtually nonexistent.

At the same time, Milan Hasek in Prague demonstrated that parabiosis of different strain chick embryos induced a immune hyporesponsive state to each other's red cells. Under prevailing Soviet scientific ideologies promoted by Lysenko and Michurin, the early publications from Hasek's laboratory (in Czech and Russian journals) explained these findings that the exchange of blood elements between chick embryos of different breeds reflected a "vegetative hybridization", a condition in which the parabionts were expected to display some of the characteristics of their partners. Later publications reflected a departure from Soviet-dominated ideologies towards immunological interpretations and Hasek and many coworkers (including T. Hraba, J. Sterzl, J. Klein, P. Ivanyi and P. Demant) have made numerous fundamental contributions to transplant immunology.

Besides neonatally induced tolerance, some investigators began to note that transplant unresponsiveness could be induced in young animals provided certain experimental conditions reflected the so-called "null" or "neutral" period concept proposed in 1956 by Billingham, Brent and Medawar. According to this concept, the immunological development of a young animal is such that exposure of antigen will neither induce immunity nor tolerance. This concept was prompted by findings that intraperitoneal inoculation of allogeneic tissues to newborn mice led to tolerance in a few and that many mice became neither immune nor tolerant. While the administration of cortisone seemed to promote tolerance, it became also apparent from data from Billingham and Brent and from Robert Good's laboratory, that the intravenous injection of adult spleen cells into newborn mice can produce long-term tolerance depending on the donor-recipient strain combination and the cell dose and timing. Few studies on blood transfusions of newborn infants had shown however, that human neonates have already a highly developed immune system and Medawar concluded that neonatally induced tolerance had no clinical applicability.

The concept of acquired tolerance had nevertheless, become deeply imbedded in the minds of transplant immunologists. Tolerance could be induced to specific histocompatibility antigens and tolerance maintenance required the continuous presence of the tolerogenic antigen as had been first demonstrated in Ray Owen's chimeric cattle model. Silvers and others reported that lymphoid cells from tolerant mice could not induce GVH reactions in donor mice and they lacked donor reactivity in MLR cultures. These findings supported the clonal deletion concept as a tolerance mechanism and Byron Waksman's studies linked the thymus gland with the events leading to the induction of tolerance to protein antigens such as bovine gamma globulin. Moreover, several experimental models showed the feasibility of tolerance induction in adult animals and other mechanisms were proposed such as "blocking" antibodies (Hellstrom) and "suppressor cells" (Gershon) and transplant immunologists began to apply the phenomenon of antibody-mediated "immunologic enhancement" of the growth of transplantable tumors in allogeneic hosts immunized with lyophilized preparations of tumor cells (Snell, Kaliss). These newly emerging concepts created a wave of investigations of many experimental models for prolonging graft survival and to define the factors responsible for these phenomena. Although these studies generated often contradictory observations that were difficult to interpret, they provided the basis of modern research efforts to unravel the complexity of the regulatory mechanisms of the immune response.

Immunosuppression.

The success of clinical transplantation depends on the control of graft rejection by immunosuppressive agents. Until the 1950s, immunosuppression in organ transplantation consisted primarily of whole-body X-irradiation. Since the beginning of the century, it was well-known that irradiation inhibited antibody responses and caused leukopenia and Dempster and co-workers in London reported in 1950 that irradiation inhibited skin allograft rejection and delayed-type hypersensitivity reactions. After the atomic bombing during worldwar II, an upsurge in radiation biology research led to an understanding of radiation-induced tissue damage and that administration of bone marrow cells provided a protection through the "generation of new areas of hematopoiesis" (Lorenz and Uphoff). These findings were important in the development of bone marrow transplantation protocols (pioneered by Donnall Thomas in Seattle) to treat leukemia patients.

During the fifties, several surgeon teams in Boston (Merrill, Murray, Hume), France (Kuss, Hamburger) and elsewhere began to transplant kidney between related individuals. Total body irradiation protocols combined later on with bone marrow infusions, produced unsatisfactory results and virtually every case failed. A 1960 editorial in the British Medical Journal concluded that "true homografts of the kidney may be expected to fail... for immunological reasons". Fortunately, basic immunologists discovered a number of drugs with immunosuppressive properties. For instance, Baker reported in 1952 the immunosuppressive effects of nitrogen mustard, but this agent was too toxic. Most promising results were obtained with an anti-mitotic agent 6-mercaptopurine synthesized by Elion and Hitchings. This drug interferes with nucleic synthesis and which had been tested to treat cancer. Schwartz and Dameshek discovered in 1959 that 6-mercaptopurine suppressed the antibody responses of rabbits to bovine serum albumin and prolonged skin allograft survival. Several investigators began to study 6-mercaptopurine in various experimental transplant models, but this drug turned out too toxic for clinical use. During his studies in Boston, the English transplant surgeon Roy Calne identified an imidazole derivative of 6-mercaptopurine (BW 57-322) which was an effective immunosuppressive drug without major adverse side effects. Also called Imuran (or Azathioprine), it became widely used as the primary anti-rejection drug in organ transplantation until the application of cyclosporine during the early 1980s.

Azathioprine could however, not be used the sole immunosuppressive agent in transplant recipients. While additional treatments included actinomycin D, azaserine and low radiation doses, the application of corticosteroid hormones produced the best results. Billingham showed in 1951 that daily administration of cortisone acetate to rabbits prolonged skin allograft survival. Thomas Starzl made the seminal observation in 1963 that large doses of prednisone can reverse rejection episodes and stabilize kidney graft function. Moreover, the combined use of azathioprine and prednisone became established procedures to manage transplant recipients until the eighties when the cyclosporine era began.

Another method of immunosuppression is the use of anti-lymphocyte antibodies raised against lymphocytes from another species. Many investigators including Metchnikoff, Flexner and Funck had already demonstrated during the early part of the century, that sera from immunized xenogeneic hosts had cytotoxic effects on leukocytes and lymphoid tissues. During the late nineteen thirties, Chew and co-workers as well as Cruickshank studied the effects of anti-lymphocyte sera raised in rabbits. These data provided the basis of the investigations two decades later, by Byron Waksman in Boston and Michael Woodruff in Edinburgh, that anti-lymphocyte serum prolonged skin allograft survival in rats. These findings were confirmed in large animal models and Starzl reported in 1968 a favorable effect of anti-lymphocyte globulin on human kidney transplant outcome. While the immunogenicity of anti-lymphocyte and anti-thymocyte globulin limits its long-term use in a clinical setting, these agents have been successfully been used to treat rejection episodes of transplant patients.

Histocompatibility Testing

Karl Landsteiner is the discoverer of the ABO red blood cell antigen system. In 1901, he published a paper on the serological reactions between sera and erythrocytes from normal individuals and he recognized two types of naturally occurring agglutinating antibodies: anti-A and anti-B. Many tissues express ABO antigens that will react with these hemagglutinins and ABO incompatibility has been avoided in organ transplantation

The Major Histocompatibility Complex controls potent transplantation antigens that elicit the rejection process. The earliest studies on the Human Leukocyte Antigen (HLA) complex (H-2 is the mouse equivalent) were done by red blood cell serologists in the 1950s. Jean Dausset in Paris recognized the immunological origin of the agglutination of white blood cells by sera from transfused patients. He identified in 1953 the first leukocyte specificity Mac, which is now called HLA-A2. Rose Payne at Stanford reported in 1958 the appearance of similar leukoagglutinating antibodies in multiparous women. Independently, Jon van Rood (Leiden, The Netherlands) made similar observations and he used computer programs for leukocyte antigen grouping from clusters of leukoagglutinating antibodies.

Since Bernard Amos had shown in 1953 that mouse H-2 antigens can be detected by leukoagglutinins, human leukocyte antigens were suspected to play a role in transplantation. Clinically, van Loghem (Amsterdam) showed in 1956, that such antibodies were associated with nonhemolytic transfusion reactions. In 1962, Felix Rapaport reported the accelerated rejection of skin grafts with leukocyte antigen mismatches.

During the early 1960s, a growing group of investigators attempted to define leukocyte antigen groups with serological techniques such as leukoagglutination and complement fixation on platelets. While these assays were lacking reproducibility, another problem was the extreme complexity of the genetics of leukocyte antigens. A turning point in the history of leukocyte typing was the intensive international collaboration that began as the First Workshop and Conference on Histocompatibility organized by Bernard Amos (Durham, NC) in 1964. This was a laboratory bench study whereby the participants compared the reactivity of their sera with various techniques. The results were so discordant that they could not be published. The Second Workshop held the following year in Leiden, yielded more coherent results and several serological specificities emerged clearly. The concept was forwarded that all of them belonged to a single, complex antigenic system analogous to the H-2 system of the mouse. Paul Terasaki and John McClelland at UCLA introduced the complement-dependent microlymphocytoxicity technique which has remained the standard serological test for HLA typing. The Third Workshop organized by Ruggero Ceppelini (Torino, Italy) in 1967, clearly established the HLA system and two segregant series of specificities (now called HLA-A and HLA-B) were recognized. The success of this international collaboration has assured the continuation of the histocompatibility workshops (Los Angeles,1970; Evian, France, 1972; Aarhus, Denmark, 1975; Oxford, 1977; Los Angeles, 1980; Munich, 1984; New York, 1987; Yokohama, 1991, and St Malo/Paris, 1996). After each workshop, a nomenclature committee has incorporated salient findings towards the definition of HLA polymorphisms including the identification of additional class I loci such as HLA-C (Thorsby, 1970), and the class II loci HLA-DR (1977) and a few years later HLA-DQ (formerly called MB) and HLA-DP (formerly SB). The latter comprise the HLA-D region which was first recognized as the MLC locus by Amos and Yunis in 1970 as a genetic system responsible for T-cell activation in the mixed leukocyte culture.

The influence of HLA matching on kidney transplant outcome was first indicted by the higher success rates of kidney transplants from HLA-identical sibling donors. During the late sixties, Terasaki, and co-workers presented early data indicating the potential beneficial effects of HLA matching on cadaveric kidney transplant survival, although these findings were based on typing information with a limited set of rather crude anti-HLA antisera. Furthermore, van Rood's group, Batchelor and Joysey, and other investigators also found that matching for HLA improves kidney and skin graft survivals. In those days, serological typing had many problems of reproducibility and lack of reagents. The conflicting presentations by Terasaki's group at the Third International Congress of the Transplantation Society in The Hague in 1970 produced considerable controversies about the significance of histocompatibility matching in kidney transplantation. Many well-matched kidney transplants failed early and conversely, badly matched kidneys did often enough function quite well. Other investigators had noted that same experience and it was not really surprising that many transplant surgeons chose to ignore tissue typing results. Of course, all these controversies arose when HLA matching was limited to an incomplete set of HLA-A and HLA-B antigens; there was no typing for HLA-DR and the available serological tests had a rather low level of reproducibility. Because of improved serological procedures and especially, the application of DNA-based techniques, HLA compatibility can now be much better defined and there remains no doubt that HLA matching correlates with less rejection and prolonged kidney transplant survival.

Histocompatibility testing for organ transplantation requires usually a crossmatch test between recipient serum and donor cells. Starzl and co-workers reported in 1965 the first case of a patient with complement-dependent anti-donor antibodies. This patient rejected almost immediately a kidney transplant from this donor and the tissue pathology suggested a Shwartzmann reaction-like mechanism. Kissmeyer-Nielsen in Copenhagen reported a similar case of what he termed a hyperacute rejction. This experience established the crossmatch test as a major test in histocompatibilty testing. The Panel-Reactive Antibody (PRA) test was first reported by Terasaki in 1971 to identify presensitized patients at higher immunological risk of rejecting their transplant.

Conclusion.

During the fifties and sixties, transplantation immunology began to emerge as a distinct scientific discipline. Six transplantation symposia were held during 1954-1964 under sponsorship of the New York Academy of Sciences and participants at these meetings included biologists, geneticists, immunologists, pathologists, surgeons and serologists. Peter Medawar concluded that "One of the distinguishing marks of modern science is the disappearance of sectarian loyalties. Isolationism is over; we all depend upon and sustain each other". The "Transplantation Society" was established in 1967 and was its membership reflected a diverse group of scientists, physicians and surgeons devoted to make transplantation as an clinically effective therapeutic modality to treat patients with end-stage disease. The diversity was also characterized by the differences in scientific concepts and experimental approaches as illustrated by the statements by two noted experts in the transplantation field ten years later. Roy Calne had the opinion that "Progress in transplantation would come less from basic immunologic research than from the search for better immunosuppressive drugs" whereas Leslie Brent stated that "The immunological solution of rejection might involve a time-scale of progress that is greater than self-interest and our natural urge for human advance demand". More than twenty years have gone by and, looking at all the accomplishments in the transplantation field, we must conclude that both men were right.

General References

·         Arthur M Silverstein: A History of Immunology, Chapter 11, "Transplantation and Immunogenetics" (Academic Press, New York, 1989).

·         Paul E. Terasaki (Editor): A History of Transplantation: Thirty-five Recollections" (UCLA Tissue Typing Laboratory Press, 1991).

·         Barry D Kahan: "Transplantation Timeline. Mankind's Three Millennia - One Maverick's Three Decades in the Struggle against Biochemical Individuality". Transplantation 51: 1-21, 1991.

·         JM Converse and PR Casson: "The Historical Background of Transplantation" In FT Rapaport and J Dausset (Editors) Human Transplantation (Grune Stratton, New York, 1968).

·         WR Clark: The Experimental Foundation of Modern Immunology, Chapter 8: "Historical Development of the Concept of the Major Histocompatibility Complexes" (4^th Edit, John Wiley, New York, 1991).

·         Paul E Terasaki (Editor): History of HLA: Ten Recollections (UCLA Tissue Typing Laboratory Press, 1990).

·         Leslie Brent: History of Transplantation Immunology (Academic Press, San Diego, CA, 1997).

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