Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1986 Nov;78(5):1415–1420. doi: 10.1172/JCI112730

Prevention of lethal murine graft versus host disease by treatment of donor cells with L-leucyl-L-leucine methyl ester.

M Charley, D L Thiele, M Bennett, P E Lipsky
PMCID: PMC423850  PMID: 3534002

Abstract

Graft vs. host disease (GVHD) remains one of the main problems associated with bone marrow transplantation. The current studies were undertaken to determine whether treatment of the donor inoculum with the anticytotoxic cell compound L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) would alter the development of GVHD in a murine model. Irradiated recipient mice transplanted with a mixture of control bone marrow and spleen cells from naive semiallogeneic donors died rapidly from GVHD, whereas the recipients of cells incubated with 250 microM Leu-Leu-OMe all survived. In addition, Leu-Leu-OMe treatment of cells obtained from donors immunized against host alloantigens resulted in significantly prolonged survival. Phenotypic characterization of spleen cells from the various groups of mice that had received Leu-Leu-OMe-treated cells and survived consistently revealed the donor phenotype. Treatment of marrow cells with 250 microM Leu-Leu-OMe appeared to have no adverse effects on stem cell function. Erythropoiesis was undiminished, as assayed by splenic 5-iodo-2'-deoxyuridine-125I uptake. Moreover, granulocytic and megakaryocytic regeneration were histologically equivalent in the spleens of recipients of control or Leu-Leu-OMe-treated cells. Treatment of the donor inoculum with Leu-Leu-OMe thus prevents GVHD in this murine strain combination with no apparent stem cell toxicity.

Full text

PDF
1415

Images in this article

1418Image
on p.1418
1418Image
on p.1418
1419Image
on p.1419
1419Image
on p.1419

Selected References

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

  1. Beatty P. G., Clift R. A., Mickelson E. M., Nisperos B. B., Flournoy N., Martin P. J., Sanders J. E., Stewart P., Buckner C. D., Storb R. Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med. 1985 Sep 26;313(13):765–771. doi: 10.1056/NEJM198509263131301. [DOI] [PubMed] [Google Scholar]
  2. Bennett M., Cudkowicz G., Foster R. S., Jr, Metcalf D. Hemopoietic progenitor cells of W anemic mice studies in vivo and in vitro. J Cell Physiol. 1968 Jun;71(3):211–226. doi: 10.1002/jcp.1040710304. [DOI] [PubMed] [Google Scholar]
  3. Charley M. R., Mikhael A., Bennett M., Gilliam J. N., Sontheimer R. D. Prevention of lethal, minor-determinate graft-host disease in mice by the in vivo administration of anti-asialo GM1. J Immunol. 1983 Nov;131(5):2101–2103. [PubMed] [Google Scholar]
  4. DeClerck Y., Draper V., Parkman R. Clonal analysis of murine graft-vs-host disease. II. Leukokines that stimulate fibroblast proliferation and collagen synthesis in graft-vs. host disease. J Immunol. 1986 May 15;136(10):3549–3552. [PubMed] [Google Scholar]
  5. Gale R. P. Graft-versus-host disease. Immunol Rev. 1985 Dec;88:193–214. doi: 10.1111/j.1600-065x.1985.tb01159.x. [DOI] [PubMed] [Google Scholar]
  6. Goldman J. M., Apperley J. F., Jones L., Marcus R., Goolden A. W., Batchelor R., Hale G., Waldmann H., Reid C. D., Hows J. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med. 1986 Jan 23;314(4):202–207. doi: 10.1056/NEJM198601233140403. [DOI] [PubMed] [Google Scholar]
  7. Hayward A. R., Murphy S., Githens J., Troup G., Ambruso D. Failure of a pan-reactive anti-T cell antibody, OKT 3, to prevent graft versus host disease in severe combined immunodeficiency. J Pediatr. 1982 Apr;100(4):665–668. doi: 10.1016/s0022-3476(82)80783-x. [DOI] [PubMed] [Google Scholar]
  8. Korngold R., Sprent J. Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow. J Exp Med. 1978 Dec 1;148(6):1687–1698. doi: 10.1084/jem.148.6.1687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Korngold R., Sprent J. Surface markers of T cells causing lethal graft-vs-host disease to class I vs class II H-2 differences. J Immunol. 1985 Nov;135(5):3004–3010. [PubMed] [Google Scholar]
  10. Ozato K., Hansen T. H., Sachs D. H. Monoclonal antibodies to mouse MHC antigens. II. Antibodies to the H-2Ld antigen, the products of a third polymorphic locus of the mouse major histocompatibility complex. J Immunol. 1980 Dec;125(6):2473–2477. [PubMed] [Google Scholar]
  11. Ozato K., Sachs D. H. Monoclonal antibodies to mouse MHC antigens. III. Hybridoma antibodies reacting to antigens of the H-2b haplotype reveal genetic control of isotype expression. J Immunol. 1981 Jan;126(1):317–321. [PubMed] [Google Scholar]
  12. Storb R., Thomas E. D. Graft-versus-host disease in dog and man: the Seattle experience. Immunol Rev. 1985 Dec;88:215–238. doi: 10.1111/j.1600-065x.1985.tb01160.x. [DOI] [PubMed] [Google Scholar]
  13. Thiele D. L., Lipsky P. E. Regulation of cellular function by products of lysosomal enzyme activity: elimination of human natural killer cells by a dipeptide methyl ester generated from L-leucine methyl ester by monocytes or polymorphonuclear leukocytes. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2468–2472. doi: 10.1073/pnas.82.8.2468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Thiele D. L., Lipsky P. E. The immunosuppressive activity of L-leucyl-L-leucine methyl ester: selective ablation of cytotoxic lymphocytes and monocytes. J Immunol. 1986 Feb 1;136(3):1038–1048. [PubMed] [Google Scholar]
  15. Tsoi M. S., Warren R. P., Storb R., Witherspoon R. P., Mickelson E., Giblett E. R., Schanfield M. S., Weiden P., Thomas E. D. Autologous marrow recovery and sensitization to non-HLA antigens after HLA-identical marrow transplantation for aplastic anemia. Exp Hematol. 1983 Jan;11(1):73–81. [PubMed] [Google Scholar]
  16. Vallera D. A., Soderling C. C., Kersey J. H. Bone marrow transplantation across major histocompatability barriers in mice. III. Treatment of donor grafts with monoclonal antibodies directed against Lyt determinants. J Immunol. 1982 Feb;128(2):871–875. [PubMed] [Google Scholar]
  17. Van Rappard-Van Der Veen F. M., Radaszkiewicz T., Terraneo L., Gleichmann E. Attempts at standardization of lupus-like graft-vs-host disease: inadvertent repopulation by DBA/2 spleen cells of H-2-different nonirradiated F1 mice. J Immunol. 1983 Jun;130(6):2693–2701. [PubMed] [Google Scholar]
  18. Vogelsang G. B., Hess A. D., Berkman A. W., Tutschka P. J., Farmer E. R., Converse P. J., Santos G. W. An in vitro predictive test for graft versus host disease in patients with genotypic HLA-identical bone marrow transplants. N Engl J Med. 1985 Sep 12;313(11):645–650. doi: 10.1056/NEJM198509123131101. [DOI] [PubMed] [Google Scholar]
  19. Wysocki L. J., Sato V. L. "Panning" for lymphocytes: a method for cell selection. Proc Natl Acad Sci U S A. 1978 Jun;75(6):2844–2848. doi: 10.1073/pnas.75.6.2844. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES