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History of clinical transplantation - PubMed

History of clinical transplantation

T E Starzl. World J Surg. 2000 Jul.

Abstract

The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations in surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft all of the organs and bone marrow cells in humans. At a more fundamental level, however, the transplantation enterprise hinged on two seminal turning points. The first was the recognition by Billingham, Brent, and Medawar in 1953 that it was possible to induce chimerism-associated neonatal tolerance deliberately. This discovery escalated over the next 15 years to the first successful bone marrow transplantations in humans in 1968. The second turning point was the demonstration during the early 1960s that canine and human organ allografts could self-induce tolerance with the aid of immunosuppression. By the end of 1962, however, it had been incorrectly concluded that turning points one and two involved different immune mechanisms. The error was not corrected until well into the 1990s. In this historical account, the vast literature that sprang up during the intervening 30 years has been summarized. Although admirably documenting empiric progress in clinical transplantation, its failure to explain organ allograft acceptance predestined organ recipients to lifetime immunosuppression and precluded fundamental changes in the treatment policies. After it was discovered in 1992 that long-surviving organ transplant recipients had persistent microchimerism, it was possible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunology could then be synthesized with which to guide efforts to induce tolerance systematically to human tissues and perhaps ultimately to xenografts.

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Figures

Fig. 1
Fig. 1

Chimerism in freemartin (fraternal twins) described by Owen [11]. Cross-tolerance to formed blood elements followed intrauterine circulatory exchange in dizygotic twins. Mutual tolerance to skin grafts was later proved by Anderson et al. with Medawar [12]. (From Starzl and Butz [13], with permission.)

Fig. 2
Fig. 2

1969 hypothesis of allograft acceptance by clonal exhaustion. Antigen presentation was depicted via the macrophages rather than by the dendritic cells (which had not yet been described). A gap in this hypothesis was the failure to stipulate the location of the immune activation. (From Starzl [139], with permission.)

Fig. 3
Fig. 3

Diffusion chamber used in studies by Algire et al. [151], from which they concluded that lymphocytes were the cellular agents of allograft rejection. (From Starzl and Butz [13], with permission.)

Fig. 4
Fig. 4

Possible mechanisms of simultaneous loss of host reactivity to specific strains of endogenous bacteria and to the alien renal tissue. (From Starzl et al. [154], with permission.)

Fig. 5
Fig. 5

Three eras of orthotopic liver transplantation at the Universities of Colorado (1963–1980) and Pittsburgh (1981–1993), defined by azathioprine-, cyclosporine-, and FK 506 (tacrolimus)-based immune suppression. The same stepwise improvement was seen with all organs. Top. Patient survival. Bottom. Graft survival. The rate here was about 10% lower than that for patient survival in both the cyclosporine (1980–1989) and tacrolimus eras (1989–1993) because of effective retransplantation, an option that did not exist previously. AZA: azathioprine; CYA: cyclosporine; TAC: tacrolimus.

Fig. 6
Fig. 6

Technique of extracorporeal perfusion with a heart-lung machine described by Marchioro et al. [220]. Catheters are inserted via the femoral vessels into the aorta and vena cava as soon as possible after death. The extracorporeal circuit is primed with a glucose or electrolyte solution to which procaine and heparin are added. The cadaver is thus anticoagulated with the first surge of the pump. Temperature control is provided by the heart exchanger. Cross-clamping the thoracic aorta limits perfusion to the lower part of the body. (From Starzl [219], with permission.)

Fig. 7
Fig. 7

Contemporaneous host-versus-graft (HVG) and graft-versus-host (GVH) reactions in the two-way paradigm of transplantation immunology. Following the initial interaction, the maintenance of nonreactivity of each leukocyte population to the other is seen as a predominantly low grade stimulatory state that may wax and wane, rather than a deletional one.

Fig. 8
Fig. 8

Top panels. One-way paradigm in which transplantation is conceived as involving a unidirectional immune reaction: host-versus-graft (HVG) with whole organs (left) and graft-versus-host (GVH) with bone marrow or other lymphopoietic transplants (right). Bottom panels. Two-way paradigm in which transplantation is seen as a bidirectional and mutually canceling immune reaction that is predominantly HVG with whole organ grafts (left) and predominantly GVH with bone marrow grafts (right).

Fig. 9
Fig. 9

Continuum of chimerism from the observations of Owen in freemartin cattle to the discovery in 1992 of microchimerism in organ recipients.

Fig. 10
Fig. 10

Four events that occur in close temporal approximation when there is successful organ engraftment. Top. Double acute clonal exhaustion (1, 2) and subsequent maintenance clonal exhaustion (3). Bottom. Loss of organ immunogenicity due to depletion of the graft’s passenger leukocytes (4).

Fig. 11
Fig. 11

Variable outcomes after infection with widely disseminated non-cytopathic viruses (or other microorganisms) and analogies (below individual graphs) to organ and bone marrow transplantation. The horizontal axis denotes time, and the vertical axis shows the viral load (V, solid line), and the host immune response (IR, dashed line).

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