Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1989 Mar 1;169(3):1031–1041. doi: 10.1084/jem.169.3.1031

Requirements for the induction and adoptive transfer of cyclosporine- induced syngeneic graft-versus-host disease

PMCID: PMC2189285  PMID: 2647891

Abstract

These studies further delineate the requirements for the establishment and transfer of SGVHD. We show that (a) two mechanisms distinguishable by radiation and drug sensitivities exist, (b) lethal irradiation correlates with a 100% incidence in the induction of SGVHD, whereas (c) both sublethal or lethal irradiation and cytoxan therapy are effective in ablating the host autoregulatory system in order to transfer autoreactivity, (d) unfractionated as well as nylon wool-nonadherent splenocytes effectively inhibit the transfer of autoimmunity, and (e) OX19 depletion of that population, however, destroys the autoregulatory effect present in normal splenocytes. To demonstrate complete inhibition of immune reactivity, twice the number of unfractionated splenocytes from normal animals was required for every splenocyte from autoimmune donors. Last, the infusion of effector splenocytes on 4, 7, and 14 d after transplantation correlates to a decrease from 100%, 70 to 0% incidence of SGVHD, thus emulating the incidence obtained in a pretransplant rat within 2 wk. These findings further clarify the immunobiological complexity of SGVHD and suggest that since autoregulatory cells already exist in normal animals that CsA-induced autoimmunity is a reflection of not an induced reactivity specific to one therapeutic reagent but the uncoupling of normal immunologic mechanisms essential in controlling autoimmunity.

Full Text

The Full Text of this article is available as a PDF (722.4 KB).

Selected References

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

  1. Beschorner W. E., Di Gennaro K. A., Hess A. D., Santos G. W. Cyclosporine and the thymus: influence of irradiation and age on thymic immunopathology and recovery. Cell Immunol. 1987 Dec;110(2):350–364. doi: 10.1016/0008-8749(87)90128-6. [DOI] [PubMed] [Google Scholar]
  2. Beschorner W. E., Tutschka P. J., Santos G. W. Sequential morphology of graft-versus-host disease in the rat radiation chimera. Clin Immunol Immunopathol. 1982 Feb;22(2):203–224. doi: 10.1016/0090-1229(82)90038-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Billingham R. E. The biology of graft-versus-host reactions. Harvey Lect. 1966;62:21–78. [PubMed] [Google Scholar]
  4. Calne R. Y. Immunosuppression for organ grafting -- observations on cyclosporin A. Immunol Rev. 1979;46:113–124. doi: 10.1111/j.1600-065x.1979.tb00286.x. [DOI] [PubMed] [Google Scholar]
  5. Engleman E. G., Benike C. J., Grumet F. C., Evans R. L. Activation of human T lymphocyte subsets: helper and suppressor/cytotoxic T cells recognize and respond to distinct histocompatibility antigens. J Immunol. 1981 Nov;127(5):2124–2129. [PubMed] [Google Scholar]
  6. Glazier A., Tutschka P. J., Farmer E. R., Santos G. W. Graft-versus-host disease in cyclosporin A-treated rats after syngeneic and autologous bone marrow reconstitution. J Exp Med. 1983 Jul 1;158(1):1–8. doi: 10.1084/jem.158.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Green C. J., Allison A. C. Extensive prolongation of rabbit kidney allograft survival after short-term cyclosporin-A treatment. Lancet. 1978 Jun 3;1(8075):1182–1183. doi: 10.1016/s0140-6736(78)90970-4. [DOI] [PubMed] [Google Scholar]
  8. Hess A. D., Horwitz L., Beschorner W. E., Santos G. W. Development of graft-vs.-host disease-like syndrome in cyclosporine-treated rats after syngeneic bone marrow transplantation. I. Development of cytotoxic T lymphocytes with apparent polyclonal anti-Ia specificity, including autoreactivity. J Exp Med. 1985 Apr 1;161(4):718–730. doi: 10.1084/jem.161.4.718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jenkins M. K., Schwartz R. H., Pardoll D. M. Effects of cyclosporine A on T cell development and clonal deletion. Science. 1988 Sep 23;241(4873):1655–1658. doi: 10.1126/science.241.4873.1655. [DOI] [PubMed] [Google Scholar]
  10. Julius M. H., Simpson E., Herzenberg L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol. 1973 Oct;3(10):645–649. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
  11. Kannourakis G., Bol S. Fractionation of normal and beta-thalassemic human hemopoietic progenitor cells by immunomagnetic beads. Exp Hematol. 1987 Dec;15(11):1103–1108. [PubMed] [Google Scholar]
  12. Mason D. W., Arthur R. P., Dallman M. J., Green J. R., Spickett G. P., Thomas M. L. Functions of rat T-lymphocyte subsets isolated by means of monoclonal antibodies. Immunol Rev. 1983;74:57–82. doi: 10.1111/j.1600-065x.1983.tb01084.x. [DOI] [PubMed] [Google Scholar]
  13. Nussenblatt R. B., Palestine A. G., Rook A. H., Scher I., Wacker W. B., Gery I. Treatment of intraocular inflammatory disease with cyclosporin A. Lancet. 1983 Jul 30;2(8344):235–238. doi: 10.1016/s0140-6736(83)90230-1. [DOI] [PubMed] [Google Scholar]
  14. Rosenkrantz K., Dupont B., Williams D., Flomenberg N. Autocytotoxic and autosuppressor T-cell lines generated from autologous lymphocyte cultures. Hum Immunol. 1987 Jul;19(3):189–203. doi: 10.1016/0198-8859(87)90069-3. [DOI] [PubMed] [Google Scholar]
  15. Sakaguchi S., Fukuma K., Kuribayashi K., Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med. 1985 Jan 1;161(1):72–87. doi: 10.1084/jem.161.1.72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sorokin R., Kimura H., Schroder K., Wilson D. H., Wilson D. B. Cyclosporine-induced autoimmunity. Conditions for expressing disease, requirement for intact thymus, and potency estimates of autoimmune lymphocytes in drug-treated rats. J Exp Med. 1986 Nov 1;164(5):1615–1625. doi: 10.1084/jem.164.5.1615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Stiller C. R., Dupré J., Gent M., Jenner M. R., Keown P. A., Laupacis A., Martell R., Rodger N. W., von Graffenried B., Wolfe B. M. Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science. 1984 Mar 30;223(4643):1362–1367. doi: 10.1126/science.6367043. [DOI] [PubMed] [Google Scholar]
  18. White D. J., Calne R. Y. The use of Cyclosporin A immunosuppression in organ grafting. Immunol Rev. 1982;65:115–131. doi: 10.1111/j.1600-065x.1982.tb00430.x. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES