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The evolution of clinical transplantation has hinged on 2 seminal turning points. The first was the demonstration in 1953 by Billingham, Brent, and Medawar that chimerism-associated tolerance could be induced deliberately in neonatal mice by infusing adult donor hematolymphopoietic cells. This discovery escalated in a straight line over the next 15 years to successful bone marrow transplantation in humans. The second turning point was the demonstration that organ allografts could self-induce tolerance under an umbrella of immunosuppression, or in some species without immunosuppression. Unfortunately, it was incorrectly concluded by most immunologists and surgeons that bone marrow and organ engraftment involved different immune mechanisms. In a derivative error, it became widely believed that the tolerogenicity of the liver differed fundamentally not only from that of bone marrow but also from that of other whole organs.
These errors became dogma and were not corrected until low level donor leukocyte chimerism was found in humans and animals bearing long surviving liver, kidney, heart, and other kinds of allografts. With successful bone marrow transplantation, the trace population consisted of recipient rather than donor leukocytes. Thus, the consequences of organ and bone marrow engraftment were mirror images. From these observations, it was proposed that the engraftment of all kinds of organs as well as bone marrow cells (BMC) involved host versus graft (HVG) and graft versus host (GVH) reactions with reciprocal induction of variable degrees of specific non-reactivity (tolerance). The maintenance of the tolerance was an active and ongoing process requiring the persistence of the transplanted fragment of the donor immune system. The immune responsiveness and unresponsiveness to both organ and bone marrow allografts are thought to be governed by the migration and localization of leukocytes. The clarifying principles of transplantation immunology that have emerged from the chimerism studies are relevant to the adaptive immune response to microbial, tumor, allogeneic, and self antigens. These principles should be used to guide efforts to systematically induce tolerance to human tissues and organs, and perhaps ultimately to xenografts.
The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations in surgical technique. Although these advances helped to make organ transplantation a practical and valuable clinical service, the feasibility of such procedures ultimately depended upon a natural quality of all organs, namely their ability to induce variable degrees of donor specific nonreactivity (i.e., tolerance).
In humans, allogeneic tolerance is a normal immunologic option that generally requires a protective umbrella of immunosuppression. However, spontaneous tolerance to organs, most commonly the liver, has been recorded in pigs, rats, and mice. In addition to its greater tolerogenicity relative to other organs, the liver is more resistant to antibody mediated hyperacute rejection. Such observations, suggesting that the liver is an "immune privileged" organ led to a controversy of more than 25 years duration. The issue was whether tolerogenicity is a unique property of the liver, or a quality possessed by all organs, varying only in degree.
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