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. 1990 Jul 1;172(1):85–94. doi: 10.1084/jem.172.1.85

Age-related factors in cyclosporine-induced syngeneic graft-versus-host disease: regulatory role of marrow-derived T lymphocytes

PMCID: PMC2188172  PMID: 2358786

Abstract

The present studies have evaluated the effect of age on the induction of syngeneic graft-versus-host disease (SGVHD) after syngeneic bone marrow transplantation (BMT) and cyclosporine (CsA) therapy. The results clearly document an inverse correlation of age with the incidence of SGVHD. Virtually a 100% incidence of SGVHD occurs in Lewis rats when syngeneic BMT and CsA therapy are started when the animals are 4 wk of age. Thereafter, there is a dramatic decline in the incidence of SGVHD with the increasing age of the animals. Although the age of the recipient was important, the most significant effect was the age of the marrow donor. Marrow from animals 6 mo of age was virtually incapable of eliciting SGVHD after BMT and CsA therapy. Furthermore, mixing the marrow from mature and immature animals resulted in a decreased incidence of SGVHD, implicating a regulatory effect present in the marrow from older rats. This regulatory effect was due to the presence of mature T cells in the marrow from animals 6 mo of age. Despite the fact that marrow from young animals possesses mature T lymphocytes, this regulatory activity was absent, suggesting that the host resistance mediated by T lymphocytes develops as the animal ages. These data further implicate the importance of a host resistance mechanism in preventing the induction of SGVHD with CsA, which appears to be mediated by the clonal inactivation of autoreactive cells.

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Selected References

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

  1. 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]
  2. Borel J. F. Comparative study of in vitro and in vivo drug effects on cell-mediated cytotoxicity. Immunology. 1976 Oct;31(4):631–641. [PMC free article] [PubMed] [Google Scholar]
  3. Borel J. F., Feurer C., Gubler H. U., Stähelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions. 1976 Jul;6(4):468–475. doi: 10.1007/BF01973261. [DOI] [PubMed] [Google Scholar]
  4. Cyclosporine. Experimental transplantation. Bone marrow. Transplant Proc. 1983 Dec;15(4 Suppl 1-2):3035–3049. [PubMed] [Google Scholar]
  5. Fischer A. C., Beschorner W. E., Hess A. D. Requirements for the induction and adoptive transfer of cyclosporine-induced syngeneic graft-versus-host disease. J Exp Med. 1989 Mar 1;169(3):1031–1041. doi: 10.1084/jem.169.3.1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fischer A. C., Laulis M. K., Horwitz L., Beschorner W. E., Hess A. Host resistance to cyclosporine induced syngeneic graft-versus-host disease. Requirement for two distinct lymphocyte subsets. J Immunol. 1989 Aug 1;143(3):827–832. [PubMed] [Google Scholar]
  7. Gao E. K., Lo D., Cheney R., Kanagawa O., Sprent J. Abnormal differentiation of thymocytes in mice treated with cyclosporin A. Nature. 1988 Nov 10;336(6195):176–179. doi: 10.1038/336176a0. [DOI] [PubMed] [Google Scholar]
  8. Hess A. D., Colombani P. M., Esa A. H. Cyclosporine and the immune response: basic aspects. Crit Rev Immunol. 1986;6(2):123–149. [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. Kojima A., Prehn R. T. Genetic susceptibility to post-thymectomy autoimmune diseases in mice. Immunogenetics. 1981;14(1-2):15–27. doi: 10.1007/BF00344296. [DOI] [PubMed] [Google Scholar]
  12. Morris P. J. Cyclosporin A. Transplantation. 1981 Nov;32(5):349–354. [PubMed] [Google Scholar]
  13. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  14. Noga S. J., Donnenberg A. D., Schwartz C. L., Strauss L. C., Civin C. I., Santos G. W. Development of a simplified counterflow centrifugation elutriation procedure for depletion of lymphocytes from human bone marrow. Transplantation. 1986 Feb;41(2):220–229. doi: 10.1097/00007890-198602000-00017. [DOI] [PubMed] [Google Scholar]
  15. Powrie F., Mason D. The MRC OX-22- CD4+ T cells that help B cells in secondary immune responses derive from naive precursors with the MRC OX-22+ CD4+ phenotype. J Exp Med. 1989 Mar 1;169(3):653–662. doi: 10.1084/jem.169.3.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Rappeport J., Mihm M., Reinherz E., Lopansri S., Parkman R. Acute graft-versus-host disease in recipients of bone-marrow transplants from identical twin donors. Lancet. 1979 Oct 6;2(8145):717–720. doi: 10.1016/s0140-6736(79)90644-5. [DOI] [PubMed] [Google Scholar]
  17. Rossini A. A., Mordes J. P., Pelletier A. M., Like A. A. Transfusions of whole blood prevent spontaneous diabetes mellitus in the BB/W rat. Science. 1983 Feb 25;219(4587):975–977. doi: 10.1126/science.6823559. [DOI] [PubMed] [Google Scholar]
  18. Sakaguchi S., Sakaguchi N. Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunol. 1989 Jan 15;142(2):471–480. [PubMed] [Google Scholar]
  19. 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]
  20. Wagner J. E., Donnenberg A. D., Noga S. J., Wiley J. M., Yeager A. M., Vogelsang G. B., Hess A. D., Santos G. W. Separation of rat bone marrow cells by counterflow centrifugal elutriation: a model for studying the effects of lymphocyte depletion. Exp Hematol. 1988 Mar;16(3):206–212. [PubMed] [Google Scholar]

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