Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Timeline
  • Published:

Transplantation tolerance from a historical perspective

Nature Reviews Immunology volume 1, pages 233–239 (2001)Cite this article

Abstract

Although transplantation immunology as a distinctive field began with the development of experimental models that showed the feasibility of bone marrow transplantation, organ engraftment was accomplished first in humans, and was thought for many years to occur by drastically different mechanisms. Here, we present our view of the concepts of allograft acceptance and acquired tolerance from a historical perspective, and attempt to amalgamate them into simple and unifying rules that might guide improvements in clinical therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Old and new views of transplantation immunology.
Figure 2: Contemporaneous HVG (upright curves) and GVH (inverted curves) responses following organ transplantation.

References

  1. Starzl, T. E. & Zinkernagel, R. M. Antigen localization and migration in immunity and tolerance. N. Engl. J. Med. 339, 1905–1913 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Brent, L. A History of Transplantation Immunology (Academic Press, London, 1997).

    Google Scholar 

  3. Burnet, F. M. & Fenner, F. The Production of Antibodies 2nd edn (Macmillan, Melbourne 1949).

    Google Scholar 

  4. Stone, H. B., Owings, J. C. & Gey, G. O. Transplantation of living grafts of thyroid and parathyroid glands. Ann. Surg. 100, 613–628 (1934).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Barker, C. F. & Billingham, R. E. The role of afferent lymphatics in the rejection of skin homografts. J. Exp. Med. 128, 197–221 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lafferty, K. J., Prowse, S. J. & Simeonovic, C. J. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu. Rev. Immunol. 1, 143–173 (1983).

    Article  CAS  PubMed  Google Scholar 

  7. Medawar, P. B. The behavior and fate of skin autografts and skin homografts in rabbits. J. Anat. 78, 176–199 (1944).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Mitchison, N. A. Passive transfer of transplantation immunity. Proc. R. Soc. Lond. B 141, 72–87 (1954).

    Google Scholar 

  9. Gorer, P. A., Lyman, S. & Snell, G. D. Studies on the genetic and antigenic basis of tumour transplantation: linkage between a histocompatibility gene and 'fused' in mice. Proc. R. Soc. Lond. B 135, 499–505 (1948).

    Article  Google Scholar 

  10. Zinkernagel, R. M. & Doherty, P. C. The discovery of MHC restriction. Immunol. Today 18, 14–17 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Owen, R. D. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 102, 400–401 (1945).

    Article  CAS  PubMed  Google Scholar 

  12. Billingham, R., Brent, L. & Medawar, P. Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance. Phil. Trans. R. Soc. Lond. B 239, 357–412 (1956).

    Article  Google Scholar 

  13. Gatti, R. A., Meuwissen, H. J., Allen, H. D., Hong, R. & Good, R. A. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet 2, 1366–1369 (1968).

    Article  CAS  PubMed  Google Scholar 

  14. Main, J. M. & Prehn, R. T. Successful skin homografts after the administration of high dosage X radiation and homologous BM. J. Natl Cancer Inst. 15, 1023–1029 (1955).

    CAS  PubMed  Google Scholar 

  15. Thomas, E. D. et al. Bone-marrow transplantation. N. Engl. J. Med. 292, 895–902 (1975).

    Article  CAS  PubMed  Google Scholar 

  16. Mathé, G., Amiel, J. L., Schwarzenberg, L., Cattan, A. & Schneider, M. Haematopoietic chimera in man after allogenic (homologous) bone-marrow transplantation. Br. Med. J. 2, 1633–1635 (1963).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Przepiorka, D., Thomas, E.D., Durham, D. M. & Fisher, L. Use of a probe to repeat sequence of the Y chromosome for detection of host cells in peripheral blood of BM transplant recipients. Am. J. Clin. Pathol. 95, 201–206 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Simonsen, M. On the acquisition of tolerance by adult cells. Ann. NY Acad. Sci. 87, 382–390 (1960).

    Article  CAS  PubMed  Google Scholar 

  19. Michie, D., Woodruff, M. F. A. & Zeiss, I. M. An investigation of immunological tolerance based on chimera analysis. Immunology 4, 413–424 (1961).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Murray, J. E. et al. Study of transplantation immunity after total body irradiation: clinical and experimental investigation. Surgery 48, 272–284 (1960).

    CAS  PubMed  Google Scholar 

  21. Hamburger, J. et al. Renal homotransplantation in man after radiation of the recipient. Am. J. Med. 32, 854–871 (1962).

    Article  CAS  PubMed  Google Scholar 

  22. Kuss, R., Legrain, M., Mathè, G., Nedey, R. & Camey, M. Homologous human kidney transplantation. Experience with six patients. Postgrad. Med. J. 38, 528–531 (1962).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schwartz, R. & Dameshek, W. Drug-induced immunological tolerance. Nature 183, 1682–1683 (1959).

    Article  CAS  PubMed  Google Scholar 

  24. Murray, J. E., Merrill, J. P., Harrison, J. H., Wilson, R. E. & Dammin, G. J. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N. Engl. J. Med. 268, 1315–1323 (1963).

    Article  CAS  PubMed  Google Scholar 

  25. Starzl, T. E., Marchioro, T. L. & Waddell, W. R. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg. Gynecol. Obstet. 117, 385–395 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Starzl, T. E. et al. The lost chord: Microchimerism. Immunol. Today 17, 577–584, 588 (1996). | PubMed |

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Starzl, T. E., Marchioro, T. L., Porter, K. A., Iwasaki, Y. & Cerilli, G. J. The use of heterologous antilymphoid agents in canine renal and liver homotransplantation and in human renal homotransplantation. Surg. Gynecol. Obstet. 124, 301–318 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Steinmuller, D. Immunization with skin isografts taken from tolerant mice. Science 158, 127–129 (1967).

    Article  CAS  PubMed  Google Scholar 

  29. Elkins, W. L. & Guttmann, R. D. Pathogenesis of a local graft versus host reaction: immunogenicity of circulating host leukocytes. Science 159, 1250–1251 (1968).

    Article  CAS  PubMed  Google Scholar 

  30. 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, 31–41 (1982).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Starzl, T. E. et al. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 17, 1127–1152 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Sterzl, J. & Silverstein, A. M. Development aspects of immunity. Adv. Immunol. 6, 337–459 (1967).

    Article  CAS  PubMed  Google Scholar 

  34. Dresser, D. W. & Mitchison, N. A. The mechanism of immunological paralysis. Adv. Immunol. 8, 129–181 (1968).

    Article  CAS  PubMed  Google Scholar 

  35. Starzl, T. E. in Experience in Hepatic Transplantation 184–190, 203–206, 227–233 (W. B. Saunders Co., Philadelphia, 1969).

    Google Scholar 

  36. Webb, S., Morris, C. & Sprent, J. Extrathymic tolerance of mature T cells: clonal chimerism elimination as a consequence of immunity. Cell 63, 1249–1256 (1990).

    Article  CAS  PubMed  Google Scholar 

  37. Moskophidis, D., Lechner, F., Pircher, H. & Zinkernagel, R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362, 758–761 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Murase, N. et al. Variable chimerism, graft-versus-host disease, and tolerance after different kinds of cell and whole organ transplantation from Lewis to brown Norway rats. Transplantation 60, 158–171 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wood, K. & Sachs, D. H. Chimerism and transplantation tolerance: cause and effect. Immunol. Today 17, 584–588 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Zinkernagel, R. M. et al. Antigen localization regulates immune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity. Immunol. Rev. 156, 199–209 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Lechler, R., Ng, W. G. & Steinman, R. M. Dendritic cells in transplantation — friend or foe? Immunity 14, 357–368 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Bumgardner, G. L., Li, J., Heininger, M., Ferguson, R. M. & Orosz, C. G. In vivo immunogenicity of purified allogeneic hepatocytes in a murine hepatocyte transplant model. Transplantation 65, 47–52 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Ochsenbein, A. F. et al. Roles of tumor-localization, second signals, and cross-priming in cytotoxic T-cell induction. Nature 411, 1058–1064 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Lakkis, F. G., Arakelov, A., Konieczny, B. T. & Inoue, Y. Immunologic ignorance of vascularized organ transplants in the absence of secondary lymphoid tissue. Nature Med. 6, 686–688 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Zinkernagel, R. M. Immunology taught by viruses. Science 271, 173–178 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Terakura, M. et al. Lymphoid/non-lymphoid compartmentalization of donor leukocyte chimerism in rat recipients of heart allografts, with or without adjunct BM. Transplantation 66, 350–357 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Ichikawa, N. et al. Donor and recipient leukocytes in organ allografts of recipients with variable donor-specific tolerance: with particular reference to chronic rejection. Liver Transpl. 6, 686–702 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Anderson, C. C. & Matzinger, P. Immunity or tolerance: opposite outcomes of microchimerism from skin grafts. Nature Med. 7, 80–87 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Shevach, E. M. Regulatory T cells in autoimmunity. Annu. Rev. Immunol. 18, 423–449 (2000).

    CAS  PubMed  Google Scholar 

  50. Waldmann, H. Transplantation tolerance — where do we stand? Nature Med. 5, 1245–1248 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Thomson, A. W. et al. Microchimerism, dendritic cell progenitors and transplantation tolerance. Stem Cells 13, 622–639 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jonuleit, H., Schmitt, E., Schuler, G., Knop, J. & Enk, A. H. Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 192, 1213–1222 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sykes, M. et al. Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplantation. Lancet 353, 1755–1759 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Monaco, A. P. et al. Possible active enhancement of human cadaver renal allograft with antilymphocyte serum (ALS) and donor bone marrow: case report of an initial attempt. Surgery 79, 384–392 (1976).

    CAS  PubMed  Google Scholar 

  55. Trivedi, H. L. et al. Megadose approach to DBMC infusion-induced allograft hyporesponsiveness in living related renal allograft recipients. Transplant Proc. 33, 71–76 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Thomas, J. M. et al. Durable donor-specific T and B cell tolerance in rhesus macaques induced with peritransplantation anti-CD3 immunotoxin and deoxyspergualin. Transplantation 69, 2497–2503 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Ramos, H. C. et al. Weaning of immunosuppression in long term liver transplant recipients. Transplantation 59, 212–217 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Takatsuki, M. et al. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation 72, 449–454 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Calne, R. et al. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation 68, 1613–1616 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Institutes of Health, the Juvenile Diabetes Research Foundation and the Swiss National Science Foundation. We gratefully acknowledge critical reviews of this manuscript by L. Brent, P. Halloran and A. Thomson and the editorial/secretarial assistance of T. Mangan.

Author information

Authors and Affiliations

  1. the Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, 15213, Pennsylvania, USA

    Thomas E. Starzl

  2. the Institut fur Experimentelle Immunologie, Universitat Zurich, Zurich, CH-8091, Switzerland

    Rolf M. Zinkernagel

Authors
  1. Thomas E. Starzl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rolf M. Zinkernagel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas E. Starzl.

Related links

Related links

DATABASES

LocusLink

CD52

CD80

CD86

Medscape DrugInfo

azathioprine

cyclosporine

6-mercaptopurine

prednisone

tacrolimus

FURTHER INFORMATION

Encyclopedia of life sciences

Graft rejection: mechanisms

transplantation

Nobel e-museum's Rolf M. Zinkernagel autobiography

Glossary

CLONAL EXHAUSTION

A state of non-reactivity when all precursor lymphocytes are induced by persistent antigen(s) to become effector cells, purging the immune-response repertoire of this specificity(s).

CLONAL SELECTION

In Burnet's original hypothesis (1949), antibody synthesis occurred after an antigen locked onto a membrane-bound receptor (a version of the antibody) at the surface of an immunocyte. In the mid-to-late 1950s, this event was postulated to be clonal by Jerne, Talmage and Burnet.

FREEMARTIN CATTLE

'Fraternal twins' whose two placentas fuse allowing fetal cross circulation, with induction of mutual specific nonreactivity.

GRAFT-VERSUS-HOST DISEASE

(GVHD). The immune reaction against a graft recipient mounted by immune-competent cells of a graft.

HOST VERSUS GRAFT

(HVG). The immune reaction mounted by the host against grafted tissue or an organ from the same species (alloresponse) or a different species (xenoresponse).

IMMUNE IGNORANCE

Failure of the immune response to recognize the presence of antigen that does not reach organized lymphoid tissue.

NEONATAL TOLERANCE

The development of specific immune non-reactivity to antigen introduced during fetal or early postnatal life, before maturation of the immune system.

NON-CYTOPATHIC MICROORGANISM

A virus, bacteria, protozoa, fungus or microparasite that does not kill host cells and can be accommodated in ways that allow the coexistence of host and pathogen.

MIXED LYMPHOCYTE REACTION

(MLR). A tissue-culture technique introduced by Barbara Bain and by Fritz Bach and Kurt Hirschorn in 1964 for in vitro testing of T-cell reactivity.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Starzl, T., Zinkernagel, R. Transplantation tolerance from a historical perspective. Nat Rev Immunol 1, 233–239 (2001). https://doi.org/10.1038/35105088

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35105088

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing