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The mystique of hepatic tolerogenicity

Starzl, TE and Murase, N and Demetris, A and Trucco, M and Fung, J (2000) The mystique of hepatic tolerogenicity. Seminars in Liver Disease, 20 (4). 497 - 510. ISSN 0272-8087

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Starzl, TEtes11@pitt.eduTES11
Murase, N
Demetris, A
Trucco, Mmnt@pitt.eduMNT
Fung, J
Centers: Other Centers, Institutes, Offices, or Units > Thomas E. Starzl Transplantation Institute
Date: 1 December 2000
Date Type: Publication
Journal or Publication Title: Seminars in Liver Disease
Volume: 20
Number: 4
Page Range: 497 - 510
DOI or Unique Handle: 10.1055/s-2000-13158
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 0272-8087
Other ID: uls-drl:31735062120401, Starzl CV No. 2128
Date Deposited: 08 Apr 2010 17:36
Last Modified: 04 Feb 2019 15:58


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