Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Liver Transpl. Author manuscript; available in PMC 2010 November 10.
Published in final edited form as:
PMCID: PMC2977908

The “Privileged” Liver and Hepatic Tolerogenicity


The mechanism underlying the immunological advantage of hepatic allografts relative to other organs is incompletely understood. We used molecular probes for the repetitive units on the Y chromosome, to identify an increasing number of male liver venous endothelial cells in needle biopsy samples of men who received female donor liver grafts. We have also shown repopulation of liver endothelium by bone marrow derived cells in a male to female mouse bone marrow transplant model. We conclude that the liver has unique venous endothelium characterized by turnover and replacement by bone marrow derived cells.


Gao et al1 have proposed that liver allografts acquire a survival advantage by the gradual replacement of their portal and central venous endothelial cells by recipient cells of bone marrow origin. The clinically based hypothesis, supported by studies of the rapid turnover and replacement of these cells in mouse radiation chimeras, is reminiscent of Woodruff’s explanation more than 4 decades ago of allograft acceptance by “… replacement of certain elements of graft, for example connective tissue stroma and vascular endothelium.”2

Several years later (in 1965), after the field of kidney transplantation had been launched with very little warning, Medawar was perplexed by the unexpected successes and wrote that “… foreign kidneys do sometimes become acceptable to their hosts for a reason other than acquired tolerance in a technical sense … One possible explanation is the progressive and perhaps very extensive replacement of the vascular endothelium of the graft by endothelium of host origin, a process that might occur insidiously and imperceptibly during a homograft reaction weakened by immunosuppressive drugs.”3

In 1971, the senior author of the current Lancet report (G.M. Williams) published the first of a series of studies of allograft vasculature, beginning with a simple model of reendothelialization of free aortic allografts with or without recipient immunosuppression with 6-mercaptopurine (6-MP).4 The endothelial replacement occurred more rapidly and completely in the non-treated animals in which rejection promptly destroyed the donor endothelium, but the same repopulation by recipient cells occurred more slowly in immunosuppression-protected allografts and in radiation chimeras analogous to those in the mouse experiments of 2001. Although the technology of 30 years ago did not provide unequivocal evidence that the replacement cells were of bone marrow origin, this possibility was considered by the investigators.4

It is clear from the human and mouse studies of Gao et al1 that endothelium is, in fact, replaced in the venous system of the liver allograft. Studies of comparable arterial changes were not described in their human liver graft specimens and were not seen in the arteries of the native parenchymal organs of mouse radiation chimeras. However, partial arterial endothelial replacement has been documented in a small number of kidney allografts after relatively short follow-ups57 and in 7 related donor kidneys studied by Randhawa et al8 that had functioned for 26 to 29 years. The patchy areas of recipient vascular endothelium in these kidneys, and in the coronary arteries of cardiac allografts described by others,9,10 were thought by Randhawa et al8 to have followed injury or rejection of the original donor cells with replacement by recipient mononuclear or endothelial progenitor cells of bone marrow origin. However, the potentially adverse implications of reendothelialization initiated by rejection or mechanical endothelial damage (eg, ischemia) do not apply with the natural turnover of endothelial cells in the liver venous system.1

The changes in both the venous and arterial system of allografts are of considerable interest. As the authors imply, however, the possible graft survival advantage should not be equated with the “hepatic tolerogenicity” that was first recognized in 1962 with the observation that nonhepatic abdominal visceral allografts in untreated dogs have a reduced severity of rejection if they are accompanied by the donor liver.11 By 1965, it was established that most canine liver recipients who survived for 4 months under azathioprine immunosuppression were tolerant (ie, no longer needed treatment to sustain graft survival). After noting that, “… the frequency and rapidity with which dogs could be withdrawn from immunosuppression is remarkable…”, it was added that, “… The consistency with which this state of host versus graft nonreactivity … seemed to develop exceeds that reported after canine renal homotransplantations … It also is important to note that cessation of therapy was not followed by a graft versus host reaction.”12

The liver allograft was subsequently shown to self-induce permanent tolerance without immunosuppression in at least 3 species: unpredictably in a significant minority of randomly paired outbred pigs,1315 invariably with a small number of strain combinations of inbred rats,16,17 and in at least 50% of experiments in about 85% of all tested mouse strain pairings.18 The self-induced tolerance is antigen-specific: ie, extends to other donor tissues and organs.1619 Although the induction of spontaneous tolerance has been widely construed to be a specific capability of the liver, donor-specific tolerance can be induced in mice by heart18,20 and kidney allografts,21 but only with a small number of strain combinations.

With the discovery in 1992 that 30 of 30 long-surviving human recipients of livers and kidneys had low-level donor leukocyte microchimerism, it was realized that organ engraftment was the product of a double immune reaction: ie, “…responses of co-existing donor and recipient cells, each to the other, causing reciprocal clonal exhaustion, followed by peripheral clonal deletion.”22,23 Although clonal exhaustion-deletion had been postulated in 1969 as the seminal basis of organ tolerogenicity24 but dismissed as an unsubstantiated theory, the existence and importance of clonal exhaustion-deletion has been established since 1990.25,26 It also was concluded that the alternative explanations of organ allograft acceptance (recently summarized by Bishop and McCaughan27) had, “… defied attempts at verification, probably because the proposed elements of each theory are simply epiphenomena of the key event: leukocyte migration and repopulation [i.e. localization].”22

It was evident that the liver is the most tolerogenic organ because of its huge content of leukocytes.22,23 Reciprocal modulation of the migratory immune competent donor leukocytes and the host immunocytes explained why graft-versus-host disease was so uncommon after clinical organ transplantation compared with the high risk of this complication in cytoablated recipients of bone marrow cells or leukocyte-rich organs. How the small number of donor leukocytes that persist after the acute posttransplant cell migration maintain the clonal exhaustion-deletion achieved at the outset has been described elsewhere in detail.28,29 The chimerism-dependent deletional tolerance and its chimerism-dependent maintenance are the crucial mechanisms for prolonged survival of any organ allograft including the liver. However, changes in the graft, such as the replacement of vascular endothelium, may be significant adjunct mechanisms.


1. Gao Z, McAllister VC, Williams M. Repopulation of liver endothelium by bone-marrow-derived cells. Lancet. 2001;357:932–933. [PubMed]
2. Woodruff MFA. Evidence of adaptation of homografts of normal tissue. In: Medawar PB, editor. Biological problems of grafting. Oxford, England: Blackwell; 1959. pp. 83–94.
3. Medawar PB. Transplantation of tissues and organs: Introduction. Br Med Bull. 1965;21:97–99.
4. Williams GM, Krajewski CA, Dagher FJ, ter Haar AM, Roth JA, Santos GW. Host repopulation of endothelium. Transplant Proc. 1971;3:869–872. [PubMed]
5. Sinclair RA. Origin of endothelium in human renal allografts. Br Med J. 1972;4:15–16. [PMC free article] [PubMed]
6. Sedmak DD, Sharma HM, Czajak CM, Ferguson RM. Recipient endothelialization of renal allografts. An immunohistochemical study utilizing blood group antigens. Transplantation. 1988;46:907–909. [PubMed]
7. Andersen CB, Ladefoged SD, Larsen S. Cellular inflammatory infiltrates and renal cell turnover in kidney allografts: A study using in situ hybridization and combined in situ hybridization and immunohistochemistry with a Y-chromosome-specific DNA probe and monoclonal antibodies. APMIS. 1991;99:645–652. [PubMed]
8. Randhawa PS, Starzl TE, Ramos H, Nalesnik MA, Demetris AJ. Allografts surviving for 26–29 years following living related kidney transplantation: Analysis by light microscopy, in situ hybridization for the Y chromosome, and anti-HLA antibodies. Am J Kidney Dis. 1994;24:72–77. [PMC free article] [PubMed]
9. O’Connell JB, Renlund DG, Bristow MR, Hammond EH. Detection of allograft endothelial cells of recipient origin following ABO-compatible, nonidentical cardiac transplantation. Transplantation. 1991;51:438–442. [PubMed]
10. Kennedy LJ, Jr, Weissman IL. Dual origin of intimal cells in cardiac-allograft arteriosclerosis. N Engl J Med. 1971;285:884–887. [PubMed]
11. Starzl TE, Kaupp HA, Jr, Brock DR, Butz GW, Jr, Linman JW. Homotransplantation of multiple visceral organs. Am J Surg. 1962;103:219–229. [PMC free article] [PubMed]
12. Starzl TE, Marchioro TL, Porter KA, Taylor PD, Faris TD, Herrmann TJ, et al. Factors determining short- and long-term survival after orthotopic liver homotransplantation in the dog. Surgery. 1965;58:131–155. [PMC free article] [PubMed]
13. Cordier G, Garnier H, Clot JP, Camplez P, Gorin JP, Clot Ph, et al. La greffe de foie orthotopique chez le porc. Mem Acad Chir (Paris) 1966;92:799–807. [PubMed]
14. Peacock JH, Terblanche J. Orthotopic homotransplantation of the liver in the pig. In: Read AE, editor. The liver. London, England: Butterworth; 1967. p. 333.
15. Calne RY, White HJO, Yoffa DE, Maginn RR, Binns RM, Samuel JR, Molina V. Observations of orthotopic liver transplantation in the pig. Br Med J. 1967;2:478–480. [PMC free article] [PubMed]
16. Kamada N, Brons G, Davies HffS. Fully allogeneic liver grafting in rats induces a state of systemic nonreactivity to donor transplantation antigens. Transplantation. 1980;29:429–431. [PubMed]
17. Zimmerman FA, Davies HS, Knoll PP, Gocke JM, Schmidt T. Orthotopic liver allografts in the rat. Transplantation. 1984;37:406–410. [PubMed]
18. Qian S, Demetris AJ, Murase N, Rao AS, Fung JJ, Starzl TE. Murine liver allograft transplantation: Tolerance and donor cell chimerism. Hepatology. 1994;19:916–924. [PMC free article] [PubMed]
19. Calne RY, Sells RA, Pena JR, Davis DR, Millard PR, Herbertson BM, et al. Induction of immunological tolerance by porcine liver allografts. Nature. 1969;223:472–474. [PubMed]
20. Corry RJ, Winn HJ, Russell PS. Primary vascularized allografts of hearts in mice. The role of H-2D, H-2K and non-H-2 antigens in rejection. Transplantation. 1973;16:343–350. [PubMed]
21. Russell PS, Chase CM, Colvin RB, Plate JMD. Kidney transplants in mice: An analysis of the immune status of mice bearing long-term H-2 incompatible transplants. J Exp Med. 1978;147:1449–1468. [PMC free article] [PubMed]
22. Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance. Lancet. 1992;339:1579–1582. [PMC free article] [PubMed]
23. Starzl TE, Demetris AJ, Trucco M, Murase N, Ricordi C, Ildstad S, et al. Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance. Hepatology. 1993;17:1127–1152. [PMC free article] [PubMed]
24. Starzl TE. Experience in hepatic transplantation. Philadelphia, PA: Saunders; 1969. Efforts to mitigate or prevent rejection; pp. 184–190.pp. 203–206.pp. 227–233.
25. Webb S, Morris C, Sprent J. Extrathymic tolerance of mature T cells: Clonal chimerism elimination as a consequence of immunity. Cell. 1990;63:1249–1256. [PubMed]
26. Moskophidis D, Lechner F, Pircher H, Zinkernagel RM. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993;362:758–761. (Erratum: Nature 1993;364:262) [PubMed]
27. Bishop GA, McCaughan GW. Immune activation is required for the induction of liver allograft tolerance: Implications for immunosuppression therapy. Liver Transpl. 2001;7:161–172. [PubMed]
28. Starzl TE, Zinkernagel RM. Antigen localization and migration in immunity and tolerance. N Engl J Med. 1998;339:1905–1913. [PMC free article] [PubMed]
29. Starzl TE, Zinkernagel RM. Regulation of transplant rejection, engraftment, and tolerance by antigen migration and localization: An historical perspective. Nat Rev Immunol. 2001 (in press).