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The essential roles of parenchymal tissues and passenger leukocytes in the tolerance induced by liver grafting in rats

Abstract

Liver allografts in pigs and rodents are uniquely capable of inducing tolerance to themselves and to other grafts of donor tissues, instead of succumbing to the acute rejection that follows transplantation of other allogeneic tissues. We demonstrate here, using normal and chimaeric rat liver grafts, that both the allogeneic liver parenchyma and the intrahepatic leukocytes of donor type contribute to the establishment of long-term tolerance, each component being essential and complementary. The essential role of hepatic parenchyma may be related to its continuous release of soluble transplantation antigens that facilitate tolerogenesis. We suggest that clinical attempts at tolerance induction by the infusion of donor bone marrow-derived leukocytes may likewise be facilitated by the coadministration of soluble transplantation antigens of donor type.

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References

  1. Calne, R.Y. et al. Induction of immunological tolerance by porcine liver allografts. Nature 223, 472–476 (1969).

    Article  CAS  Google Scholar 

  2. Zimmermann, F.A., Davies, H.ff.S., Knoll, P.P., Gokel, J.M. & Schmidt, T. Orthotopic liver allografts in the rat: the influence of strain combination on the fate of the graft. Transplantation 37, 406–412 (1984).

    Article  CAS  Google Scholar 

  3. Millard, P.R., Herbertson, B.M. & Calne, R.Y. Morphological features of kidney and liver allografts in the pig. Transplant. Proc. 3, 505–508 (1971).

    CAS  PubMed  Google Scholar 

  4. Kamada, N., Davies, H.ff.S., Wight, D., Culank, L. & Roser, B.J. Liver transplantation in the rat: Biochemical and histological evidence of complete tolerance induction in nonrejector strains. Transplantation 35, 304–311 (1983).

    Article  CAS  Google Scholar 

  5. Davies, H.ff.S., Kamada, N. & Roser, B.J. Mechanisms of donor-specific unresponsiveness induced by liver grafting. Transplant. Proc. 15, 831–835 (1983).

    Google Scholar 

  6. Calne, R.Y. Strategies in tolerance and liver transplantation. Clin. Transplantation 5, 544–548 (1991).

    Google Scholar 

  7. Kamada, N., Brons, I.G.M. & Davies, H.ff.S. Fully allogeneic liver grafting in rats induces a state of systemic nonreactivity to donor transplantation antigens. Transplantation 29, 429–431 (1980).

    Article  CAS  Google Scholar 

  8. Qian, S. et al. Murine liver allograft transplantation: tolerance and donor cell chimerism. Hepatology 19, 916–924 (1994).

    Article  CAS  Google Scholar 

  9. Starzl, T.E. et al. Cell migration, chimerism and graft acceptance. Lancet 339, 1579–1582 (1992).

    Article  CAS  Google Scholar 

  10. Starzl, T.E. et al. Cell chimerism permitted by immunosuppressive drugs is the basis of organ transplant acceptance and tolerance. Immunol. Today 14, 326–332 (1993).

    Article  CAS  Google Scholar 

  11. Starzl, T.E. et al. Chimerism and donor specific nonreactivity 27 to 29 years after kidney allotransplantation. Transplantation 55, 1272–1277 (1993).

    Article  CAS  Google Scholar 

  12. Lechler, R.I. & Batchelor, J.R. Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells. J. exp. Med. 155, 31–37 (1982).

    Article  CAS  Google Scholar 

  13. Sriwatanawongsa, V. et al. Continued presence of donor leukocytes in recipients of liver grafts. Transplant. Proc. 25, 371–372 (1993).

    CAS  PubMed  Google Scholar 

  14. Settaf, A., Milton, A.D., Spencer, S.C., Houssin, D. & Fabre, J.W. Donor class I and class I major histocompatibility complex antigen expression following liver allografting in rejecting and nonrejecting rat strain combinations. Transplantation 46, 32 (1988).

    Article  CAS  Google Scholar 

  15. Sriwatanawongsa, V., Davies, H.ff.S. & Calne, R.Y. Successful retransplantation of rat liver grafts. Transplantation (in the press).

  16. Kamada, N., Davies, H.ff.S. & Roser, B.J. Reversal of transplantation immunity by liver grafting. Nature 292, 840–842 (1981).

    Article  CAS  Google Scholar 

  17. Davies, H.ff.S., Pollard, S.G. & Calne, R.Y. Soluble HLA antigens in the circulation of liver graft recipients. Transplantation 47, 524–527 (1989).

    Article  CAS  Google Scholar 

  18. Zavazava, N., Haussmann, R., Kraatz, E. & Muller-Ruchholz, W. Clinical relevance of soluble HLA and interaction of papain derived class I molecules with alloreactive CTL. Transplant. Int. 5 (supp.l 1), 606–608 (1992).

    Article  Google Scholar 

  19. Davies, H.ff.S., Pollard, S.G. & Calne, R.Y. Tolerogenic and immunosuppressive properties of liver grafts in animals and man. Transplant. Proc. 23, 2248–2249 (1991).

    CAS  PubMed  Google Scholar 

  20. Priestly, C.A., Dalchau, R., Sawyer, G.J. & Fabre, J.W. A detailed analysis of the potential of water soluble class I molecules for the suppression of kidney allograft rejection and in vitro cytotoxic T cell responses. Transplantation 48, 1031–1038 (1989).

    Article  Google Scholar 

  21. Spencer, S.C. & Fabre, J.W. Water soluble and membrane bound forms of RT1-A (H-2K, D type) class I molecules in the kidney and liver of the rat. Immunogenetics 25, 91–96 (1987).

    Article  CAS  Google Scholar 

  22. Singh, P.B., Brown, R.E. & Roser, B. class I transplantation antigens in solution in body fluids and in the urine. J. exp. Med. 168, 195–211 (1988).

    Article  CAS  Google Scholar 

  23. Sumimoto, R. & Kamada, N. Specific suppression of allograft rejection by soluble class I antigen and complexes with monoclonal antibody. Transplantation 50, 678–682 (1990).

    Article  CAS  Google Scholar 

  24. Batchelor, J.R., Welsh, K.I., Maynard, A. & Burgos, H. Failure of long surviving, passively enhanced kidney allografts to provoke T-dependent alloimmunity. I. Retransplantation of (ASxAUG)F1 kidneys into secondary AS recipients. J. exp. Med. 150, 455–464 (1979).

    Article  CAS  Google Scholar 

  25. Demetris, A.J., Murase, N., Rao, A.S. & Starzl, T.E. The role of passenger leukocytes in rejection and “tolerance” after solid organ transplantation: a potential explanation of a paradox. In Rejection & Tolerance, (eds Touraine J.L. et al.) 325–392 (Kluwer Academic, Dordrecht. 1994).

    Chapter  Google Scholar 

  26. Dahmen, U. et al. Split tolerance induced by orthotopic liver transplantation in mice. Transplantation 58, 1–8 (1994).

    Article  CAS  Google Scholar 

  27. Rasmussen, A., Davies, H.ff.S., Jamieson, N.V., Evans, D.B. & Calne, R.Y. Combined transplantation of liver and kidney from the same donor protects the kidney from rejection and improves kidney graft survival. Transplantation (in the press).

  28. Calne, R.Y. et al. Tolerance of porcine renal allografts induced with donor spleen cells and seven days treatment with cyclosporine. Transplantation 57, 1433–1435 (1994).

    Article  CAS  Google Scholar 

  29. Fontes, P. et al. Augmentation with bone marrow of donor leukocyte migration for kidney, liver, heart, and pancreas islet transplantation. Lancet 344, 151–155 (1994).

    Article  CAS  Google Scholar 

  30. Calne, R. & Davies, H. Organ graft tolerance: the liver effect. Lancet, 343, 67–68 (1994).

    Article  CAS  Google Scholar 

  31. Zimmermann, F.A. et al. Techniques for orthotopic liver transplantation in the rat and some studies of the immunological responses to fully allogeneic liver grafts. Transplant. Proc. 11, 571–577 (1979).

    CAS  PubMed  Google Scholar 

  32. Kamada, N. & Calne, R.Y. A surgical experience with 530 liver transplants in the rat. Surgery 93, 64–73 (1983).

    CAS  PubMed  Google Scholar 

  33. Butcher, G.W. A list of monoclonal antibodies specific for alloantigens of the rat. J. Immunogenet. 14, 163–176 (1987).

    Article  CAS  Google Scholar 

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Sriwatanawongsa, V., Davies, H. & Calne, R. The essential roles of parenchymal tissues and passenger leukocytes in the tolerance induced by liver grafting in rats. Nat Med 1, 428–432 (1995). https://doi.org/10.1038/nm0595-428

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