Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Mar;91(3):900–906. doi: 10.1172/JCI116311

Analysis of T cell responses in liver allograft recipients. Evidence for deletion of donor-specific cytotoxic T cells in the peripheral circulation.

J M Mathew 1, J W Marsh 1, B Susskind 1, T Mohanakumar 1
PMCID: PMC288042  PMID: 8450068

Abstract

Analysis of cell-mediated lympholysis in long-term liver allograft recipients indicated that there was a donor-specific unresponsiveness that could not be reversed by the addition of rIL-2 and/or mixed lymphocyte culture supernatant or by nonspecific stimulation of the cultures with PHA. Stimulation of recipient cells with semisyngeneic cells having both donor and third-party HLA antigens failed to reveal the presence of cytotoxic T cells (CTL) specific to the donor, whereas the CTL response to third-party antigens remained normal. Removal of B lymphocytes from the responding cell population did not influence the responses. Furthermore, limiting dilution analysis showed that the liver transplant recipients did not have detectable levels of CTL precursors (CTLp) reactive to the donor antigens, whereas their CTLp to third-party antigens remained normal. Donor-specific CTLp were present before and during the early post-transplant period; these cells were eliminated from the peripheral circulation by 10 mo after transplantation. Taken together, these results indicate that there is a deletion of CTLp specific to donor MHC antigens in the peripheral circulation of long-term liver allograft recipients that may account in part for the success of liver transplantation across MHC barriers.

Full text

PDF
900

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Calne R. Y., Sells R. A., Pena J. R., Davis D. R., Millard P. R., Herbertson B. M., Binns R. M., Davies D. A. Induction of immunological tolerance by porcine liver allografts. Nature. 1969 Aug 2;223(5205):472–476. doi: 10.1038/223472a0. [DOI] [PubMed] [Google Scholar]
  2. Cohen D. J., Lee H. M., Mohanakumar T. Mechanisms of CML hyporesponsiveness in long-term renal allograft recipients. Hum Immunol. 1985 Nov;14(3):279–286. doi: 10.1016/0198-8859(85)90235-6. [DOI] [PubMed] [Google Scholar]
  3. Davies H. S., Pollard S. G., Calne R. Y. Soluble HLA antigens in the circulation of liver graft recipients. Transplantation. 1989 Mar;47(3):524–527. doi: 10.1097/00007890-198903000-00025. [DOI] [PubMed] [Google Scholar]
  4. Demetris A. J., Lasky S., Van Thiel D. H., Starzl T. E., Whiteside T. Induction of DR/IA antigens in human liver allografts. An immunocytochemical and clinicopathologic analysis of twenty failed grafts. Transplantation. 1985 Nov;40(5):504–509. doi: 10.1097/00007890-198511000-00007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Demetris A. J., Markus B. H. Immunopathology of liver transplantation. Crit Rev Immunol. 1989;9(2):67–92. [PubMed] [Google Scholar]
  6. Dumble L. J., MacDonald I. M., Kincaid-Smith P. Human renal allograft rejection is predicted by serial determinations of antibody-dependent cellular cytotoxicity. Transplantation. 1980;29(1):30–34. doi: 10.1097/00007890-198001000-00007. [DOI] [PubMed] [Google Scholar]
  7. Flye M. W., Duffy B. F., Phelan D. L., Ratner L. E., Mohanakumar T. Protective effects of liver transplantation on a simultaneously transplanted kidney in a highly sensitized patient. Transplantation. 1990 Dec;50(6):1051–1054. [PubMed] [Google Scholar]
  8. Grailer A. P., Sollinger H. W., Kawamura T., Burlingham W. J. Donor-specific cytotoxic T lymphocyte hyporesponsiveness following renal transplantation in patients pretreated with donor-specific transfusions. Transplantation. 1991 Feb;51(2):320–324. doi: 10.1097/00007890-199102000-00009. [DOI] [PubMed] [Google Scholar]
  9. Hadley G. A., Phelan D., Duffy B. F., Mohanakumar T. Lack of T-cell tolerance of noninherited maternal HLA antigens in normal humans. Hum Immunol. 1990 Aug;28(4):373–381. doi: 10.1016/0198-8859(90)90032-k. [DOI] [PubMed] [Google Scholar]
  10. Kamada N., Brons G., Davies H. S. Fully allogeneic liver grafting in rats induces a state of systemic nonreactivity to donor transplantation antigens. Transplantation. 1980 May;29(5):429–431. doi: 10.1097/00007890-198005000-00021. [DOI] [PubMed] [Google Scholar]
  11. Kamada N., Shinomiya T. Clonal deletion as the mechanism of abrogation of immunological memory following liver grafting in rats. Immunology. 1985 May;55(1):85–90. [PMC free article] [PubMed] [Google Scholar]
  12. Kamada N., Shinomiya T., Tamaki T., Ishiguro K. Immunosuppressive activity of serum from liver-grafted rats. Passive enhancement of fully allogeneic heart grafts and induction of systemic tolerance. Transplantation. 1986 Dec;42(6):581–587. doi: 10.1097/00007890-198612000-00002. [DOI] [PubMed] [Google Scholar]
  13. Kamada N. The immunology of experimental liver transplantation in the rat. Immunology. 1985 Jul;55(3):369–389. [PMC free article] [PubMed] [Google Scholar]
  14. Kamada N., Wight D. G. Antigen-specific immunosuppression induced by liver transplantation in the rat. Transplantation. 1984 Sep;38(3):217–221. doi: 10.1097/00007890-198409000-00004. [DOI] [PubMed] [Google Scholar]
  15. Liburd E. M., Pazderka V., Kovithavongs T., Dossetor J. B. Evidence for suppressor cells and reduced CML induction by the donor in transplant patients. Transplant Proc. 1978 Sep;10(3):557–561. [PubMed] [Google Scholar]
  16. Loveland B., Ceredig R., Hogarth M., McKenzie I. The key role of Lyt-1+ cells in skin graft rejection in the mouse. Transplant Proc. 1981 Mar;13(1 Pt 2):1079–1081. [PubMed] [Google Scholar]
  17. Mohanakumar T., Rhodes C., Mendez-Picon G., Flye M. W., Lee H. M. Antiidiotypic antibodies to human major histocompatibility complex class I and II antibodies in hepatic transplantation and their role in allograft survival. Transplantation. 1987 Jul;44(1):54–58. doi: 10.1097/00007890-198707000-00013. [DOI] [PubMed] [Google Scholar]
  18. Schutze M. P., Langlade-Demoyen P., Leclerc C. Alloantigen-specific regulation of cytotoxic T cell responses is mediated through the induction of clonal anergy of CD8+ T cells. Eur J Immunol. 1992 Feb;22(2):387–392. doi: 10.1002/eji.1830220215. [DOI] [PubMed] [Google Scholar]
  19. Susskind B. M. Regulatory mechanisms in cytotoxic T lymphocyte development. III. Induction, specificity, and genetic restriction of an in vitro suppressor T cell. Cell Immunol. 1986 Sep;101(2):524–533. doi: 10.1016/0008-8749(86)90163-2. [DOI] [PubMed] [Google Scholar]
  20. Tsuchimoto S., Kakita A., Uchino J., Mizuno K., Niiyama T., Fujii H., Matsuno Y., Natori T., Aizawa M. Mechanism of tolerance in rat liver transplantation: evidence for the existence of suppressor cells. Transplant Proc. 1987 Feb;19(1 Pt 1):514–518. [PubMed] [Google Scholar]
  21. Uberti J., Martilotti F., Chou T. H., Kaplan J. Human lymphokine activated killer (LAK) cells suppress generation of allospecific cytotoxic T cells: implications for use of LAK cells to prevent graft-versus-host disease in allogeneic bone marrow transplantation. Blood. 1992 Jan 1;79(1):261–268. [PubMed] [Google Scholar]
  22. Vandekerckhove B. A., Datema G., Koning F., Goulmy E., Persijn G. G., Van Rood J. J., Claas F. H., De Vries J. E. Analysis of the donor-specific cytotoxic T lymphocyte repertoire in a patient with a long term surviving allograft. Frequency, specificity, and phenotype of donor-reactive T cell receptor (TCR)-alpha beta+ and TCR-gamma delta+ clones. J Immunol. 1990 Feb 15;144(4):1288–1294. [PubMed] [Google Scholar]
  23. van Twuyver E., Kast W. M., Mooijaart R. J., Wilmink J. M., Melief C. J., de Waal L. P. Allograft tolerance induction in adult mice associated with functional deletion of specific CTL precursors. Transplantation. 1989 Nov;48(5):844–847. doi: 10.1097/00007890-198911000-00024. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES