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. 1989 Jul;77(1):151–156.

Alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, augments cyclosporin A inhibition of cytolytic T lymphocyte induction.

T L Bowlin 1, A L Rosenberger 1, B J McKown 1
PMCID: PMC1541926  PMID: 2504519

Abstract

The objective of the present investigation was to examine the effect of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, in combination with the immunosuppressant cyclosporin A (CsA) on cytolytic T lymphocytes (CTL) induction in vitro and in vivo. Treatment with DFMO (0.2 mg/ml) or CsA (10 ng/ml) alone in vitro inhibited mitogen-induced CTL generation by 56% and 51%, respectively. Similarly, DFMO or CsA treatment alone inhibited alloantigen-induced CTL generation by 50% and 62%, respectively. Combination treatment with DFMO and CsA reduced mitogen- and alloantigen-mediated CTL induction by 79% and 90%, respectively. In vivo, DFMO treatment alone did not inhibit alloantigen induced CTL generation. However, DFMO potentiated the immunosuppressive effects of CsA in vivo on CTL induction. DFMO treatment reduced activated lymphocyte putrescine and spermidine levels by 81% and 91%, respectively. Combination treatment with DFMO and CsA, at concentrations that effectively inhibited CTL induction, did not further deplete polyamine levels beyond those levels observed with DFMO alone. CsA treatment with or without DFMO did reduce detectable levels of interleukin 2 (IL-2) activity. DFMO treatment alone did not impair IL-2 production. These results indicate that CsA and DFMO may inhibit different processes required for CTL induction, IL-2 production and polyamine biosynthesis. Therefore, inhibitors of polyamine biosynthesis may be useful in lowering the doses of CsA required to inhibit CTL induction.

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Selected References

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

  1. Baker P. E., Gillis S., Ferm M. M., Smith K. A. The effect of T cell growth factor on the generation of cytolytic T cells. J Immunol. 1978 Dec;121(6):2168–2173. [PubMed] [Google Scholar]
  2. Bowlin T. L., Davis G. F., McKown B. J. Inhibition of alloantigen-induced cytolytic T lymphocytes in vitro with (2R,5R)-6-heptyne-2,5-diamine, an irreversible inhibitor of ornithine decarboxylase. Cell Immunol. 1988 Feb;111(2):443–450. doi: 10.1016/0008-8749(88)90107-4. [DOI] [PubMed] [Google Scholar]
  3. Bowlin T. L., McKown B. J., Babcock G. F., Sunkara P. S. Intracellular polyamine biosynthesis is required for interleukin 2 responsiveness during lymphocyte mitogenesis. Cell Immunol. 1987 May;106(2):420–427. doi: 10.1016/0008-8749(87)90184-5. [DOI] [PubMed] [Google Scholar]
  4. Bowlin T. L., McKown B. J., Davis G. F., Sunkara P. S. Effect of polyamine depletion in vivo by DL-alpha-difluoromethylornithine on functionally distinct populations of tumoricidal effector cells in normal and tumor-bearing mice. Cancer Res. 1986 Nov;46(11):5494–5498. [PubMed] [Google Scholar]
  5. Bowlin T. L., McKown B. J., Sunkara P. S. Increased ornithine decarboxylase activity and polyamine biosynthesis are required for optimal cytolytic T lymphocyte induction. Cell Immunol. 1987 Mar;105(1):110–117. doi: 10.1016/0008-8749(87)90060-8. [DOI] [PubMed] [Google Scholar]
  6. Bowlin T. L., McKown B. J., Sunkara P. S. Ornithine decarboxylase induction and polyamine biosynthesis are required for the growth of interleukin-2- and interleukin-3-dependent cell lines. Cell Immunol. 1986 Apr 1;98(2):341–350. doi: 10.1016/0008-8749(86)90294-7. [DOI] [PubMed] [Google Scholar]
  7. Bowlin T. L., McKown B. J., Sunkara P. S. The effect of alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, on mitogen-induced interleukin 2 production. Immunopharmacology. 1987 Apr;13(2):143–147. doi: 10.1016/0162-3109(87)90051-8. [DOI] [PubMed] [Google Scholar]
  8. Britton S., Palacios R. Cyclosporin A--usefulness, risks and mechanism of action. Immunol Rev. 1982;65:5–22. doi: 10.1111/j.1600-065x.1982.tb00425.x. [DOI] [PubMed] [Google Scholar]
  9. Bunjes D., Hardt C., Röllinghoff M., Wagner H. Cyclosporin A mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of interleukin 1 and interleukin 2. Eur J Immunol. 1981 Aug;11(8):657–661. doi: 10.1002/eji.1830110812. [DOI] [PubMed] [Google Scholar]
  10. Ehrke M. J., Porter C. W., Eppolito C., Mihich E. Selective modulation by alpha-difluoromethylornithine of T-lymphocyte and antibody-mediated cytotoxic responses to mouse tumor allografts. Cancer Res. 1986 Jun;46(6):2798–2803. [PubMed] [Google Scholar]
  11. Elliott J. F., Lin Y., Mizel S. B., Bleackley R. C., Harnish D. G., Paetkau V. Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science. 1984 Dec 21;226(4681):1439–1441. doi: 10.1126/science.6334364. [DOI] [PubMed] [Google Scholar]
  12. Fidelus R. K., Laughter A. H., Twomey J. J., Taffet S. M., Haddox M. K. The effect of cyclosporine on ornithine decarboxylase induction with mitogens, antigens, and lymphokines. Transplantation. 1984 Apr;37(4):383–387. doi: 10.1097/00007890-198404000-00014. [DOI] [PubMed] [Google Scholar]
  13. Fidelus R. K., Laughter A. H., Twomey J. J. The role of mitogens and lymphokines in the induction of ornithine decarboxylase (ODC) in T lymphocytes. J Immunol. 1984 Mar;132(3):1462–1465. [PubMed] [Google Scholar]
  14. Fillingame R. H., Jorstad C. M., Morris D. R. Increased cellular levels of spermidine or spermine are required for optimal DNA synthesis in lymphocytes activated by concanavalin A. Proc Natl Acad Sci U S A. 1975 Oct;72(10):4042–4045. doi: 10.1073/pnas.72.10.4042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Granelli-Piperno A., Inaba K., Steinman R. M. Stimulation of lymphokine release from T lymphoblasts. Requirement for mRNA synthesis and inhibition by cyclosporin A. J Exp Med. 1984 Dec 1;160(6):1792–1802. doi: 10.1084/jem.160.6.1792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kay J. E., Lindsay V. J. Polyamine synthesis during lymphocyte activation. Induction of ornithine decarboxylase and S-adenosyl methionine decarboxylase. Exp Cell Res. 1973 Mar 15;77(1):428–436. doi: 10.1016/0014-4827(73)90597-1. [DOI] [PubMed] [Google Scholar]
  17. Klimpel G. R., Byus C. V., Russell D. H., Lucas D. O. Cyclic AMP-dependent protein kinase activation and the induction of ornithine decarboxylase during lymphocyte mitogenesis. J Immunol. 1979 Aug;123(2):817–824. [PubMed] [Google Scholar]
  18. Krönke M., Leonard W. J., Depper J. M., Arya S. K., Wong-Staal F., Gallo R. C., Waldmann T. A., Greene W. C. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5214–5218. doi: 10.1073/pnas.81.16.5214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Morgan D. A., Ruscetti F. W., Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science. 1976 Sep 10;193(4257):1007–1008. doi: 10.1126/science.181845. [DOI] [PubMed] [Google Scholar]
  20. Sjoerdsma A., Schechter P. J. Chemotherapeutic implications of polyamine biosynthesis inhibition. Clin Pharmacol Ther. 1984 Mar;35(3):287–300. doi: 10.1038/clpt.1984.33. [DOI] [PubMed] [Google Scholar]
  21. Szamel M., Berger P., Resch K. Inhibition of T lymphocyte activation by cyclosporin A: interference with the early activation of plasma membrane phospholipid metabolism. J Immunol. 1986 Jan;136(1):264–269. [PubMed] [Google Scholar]
  22. Wang B. S., Heacock E. H., Collins K. H., Hutchinson I. F., Tilney N. L., Mannick J. A. Suppressive effects of cyclosporin A on the induction of alloreactivity in vitro and in vivo. J Immunol. 1981 Jul;127(1):89–93. [PubMed] [Google Scholar]

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