Advertisement

Cyclosporin pp 24-33 | Cite as

Effect of cyclosporin A on the immune response: pivotal role of the interleukin-2/ interleukin-2 receptor autocrine pathway

  • Allan D. Hess

Abstract

In 1976 Borel first described the potent immunosuppressive activity of cyclosporin A (CsA) and its apparent selective action on T lymphocyte-dependent cell-mediated immune responses1,2. Within a decade of these initial observations CsA has become the front-line immunosuppressive agent to prevent solid organ graft rejection and graft-versus-host disease in clinical transplantation3. Its usefulness is currently being evaluated in a wide variety of autoimmune disorders with some remarkable successes4,5. Despite the wide empiric application of CsA, the precise mechanism of action of this drug remains elusive. Nevertheless, many studies have provided some insight into the action of this unique immunosuppressive drug on the cells of the immune system which mediate the events of graft rejection. It has become increasingly apparent that one of the primary actions of CsA is on the interleukin-2 (IL-2)/interleukin-2 receptor autocrine pathway. This chapter will attempt to summarize the salient features of the effects of CsA on the complex cellular events necessary for a competent immune response with a particular focus on the IL-2/IL-2 receptor pathway.

Keywords

Graft Rejection Lymphokine Production Clonal Amplification Potent Immunosuppressive Activity Alloantigen Stimulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Borel, J. F. (1976) Comparative study of in vitro and in vivo drug effects on cell-mediated cytotoxicity. Immunology, 31, 631PubMedGoogle Scholar
  2. 2.
    Borel, J. F., Feurer, C., Gubler, H. U. and Stahelin, H. (1976) Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions, 6, 468PubMedCrossRefGoogle Scholar
  3. 3.
    Morris, P. J. (1981) Cyclosporin A. Transplantation, 32, 349PubMedCrossRefGoogle Scholar
  4. 4.
    Schindler, R. (ed.) (1985) Ciclosporin in Autoimmune Diseases (Berlin: Springer-Verlag)Google Scholar
  5. 5.
    Stiller, G R., Durpe, J., Gent, M., jenner, M. R., Keown, P. A., Laupacis, A., Martell, R., Rodger, N. W., von Graffenreid, B. and Wolfe, B. M. J. (1984) Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science, 223, 1362PubMedCrossRefGoogle Scholar
  6. 6.
    Hess, A. D., Colombani, P. M. and Esa, A H. (1986) Cyclosporin and the immune response: basic aspects. Crit. Rev. Immunol., 6, 123PubMedGoogle Scholar
  7. 7.
    Green, G. L. and Allison, A. C. (1978) Extensive prolongation of rabbit kidney allograft survival after short-term Cyclosporin A treatment. Lancet, 1, 1182PubMedCrossRefGoogle Scholar
  8. 8.
    Hess, A. D., Esa, A. H. and Colombani, P. M. (1985) Mechanisms of action of cyclosporine: Effect on cells of the immune system and on subcellular events in T cell activation. Trans. Proc., 20 (Suppl. 2), 29Google Scholar
  9. 9.
    Bunjes, D., Hardt, C., Rollinghoff, M. and Wagner, H. (1981) Cyclosporin A mediates immunosuppesslon, of primary cytotoxic T cell responses by impairing the release of interleukin 1 and interleukin 2. Eur. J. Immunol., 8, 657CrossRefGoogle Scholar
  10. 10.
    Hess, A. D., Tutschka, P. J., Pu, Z. and Santos, G. W. (1982) Effect of cyclosporine A on human lymphocyte responses in vitro. IV. Production of stimulatory growth factor in CsA treated primary MLR cultures. J. Immunol., 128, 360PubMedGoogle Scholar
  11. 11.
    Hess, A. D. (1985) Effect of interleukin 2 on the immunosuppressive action of cyclosporine. Transplantation, 39, 62PubMedCrossRefGoogle Scholar
  12. 12.
    Thomson, A. W., Moon, D. K. and Nelson, D. S. (1983) Suppression of delayed type hypersensitivity reactions and lymphokine production by cyclosporin A in the mouse. Clin. Exp. Immunol., 52, 599PubMedGoogle Scholar
  13. 13.
    Wang, G. S., Zheng, C., Heacock, E. H., Tilney, N. L., Strom, T. B. and Mannick, J. A. (1983) Inhibition of the production of a soluble helper mediator by cyclosporin A results in the failure to generate alloreactive cytolytic cells in mixed-lymphocyte culture. Clin. Immunol Immunopathol., 27, 160PubMedCrossRefGoogle Scholar
  14. 14.
    Hess, A. D., Tutschka, P. J. and Santos, G. W. (1983) Effect of cyclosporine on the induction of cytotoxic T lymphocytes: Role of interleukin 1 and interleukin 2. Transplant. Proc., 15, 2248Google Scholar
  15. 15.
    Palacios, R. and Moller, G. (1981) Cyclosporin A blocks receptors for HLA-DR antigens on T cells. Nature, 290, 792PubMedCrossRefGoogle Scholar
  16. 16.
    Andrus, L. and Lafferty, K. J. (1981) Inhibition of T-cell activity by cyclosporin A. Scand. J. Immunol., 15, 449PubMedCrossRefGoogle Scholar
  17. 17.
    Hess, A. D., Tutschka, P. J. and Santos, G. W. (1982) Effect of cyclosporin on human lymphocyte response in vitro. III. CS inhibits the production of T lymphocyte growth factors in secondary mixed lymphocyte responses but does not inhibit the response of primed lymphocytes to TCGF. J. Immunol., 128, 355PubMedGoogle Scholar
  18. 18.
    Elliott, J. F., Lin, Y., Mizel, S. B., BleacHey, R. C., Hamish, D. G. and Paetkau, V. (1984) Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science, 226, 1439PubMedCrossRefGoogle Scholar
  19. 19.
    Granelli-Pipemo, A., Inaba, K. and Steinman, R. (1984) Stimulation of lymphokine release from T lymphoblasts. Requirement for mRNA synthesis and inhibition by cyclosporin A. J. Exp. Med., 160, 1792CrossRefGoogle Scholar
  20. 20.
    Granelli-Pipemo, A. (1988) In situ hybridization for interleukin 2 and interleukin 2 receptor mRNA in T cells activated in the presence and absence of CsA.J. Exp. Med., 168, 1649CrossRefGoogle Scholar
  21. 21.
    Borel, J. F. and Ryffel, B. (1986) The mechanism of action of cyclosporin: a continuing puzzle. In Schindler, R. (ed.), Ciclosporin in Autoimmune Diseases, (Berlin: Springer-Verlag), pp. 24–32Google Scholar
  22. 22.
    Weissm, A. and Imboden, J. (1987) Cell surface molecules and early events in T lymphocyte activation. Adv. Immunol., 41, 1CrossRefGoogle Scholar
  23. 23.
    Hodgkin, P. D., Hapel, A. J., Johnson, R. M., Young, I. G. and Lafferty, K. J. (1987) Blocking of the delivery of the antigen-mediated signal to the nucleus of T cells by Cyclosporine. Transplantation, 43, 685PubMedCrossRefGoogle Scholar
  24. 24.
    Citterio, F. and Kahan, B. P. (1988) Effects of cyclosporine on nuclear function. Trans. Proc., 20 (Suppl. 2), 75Google Scholar
  25. 25.
    June, C H., Ledbetter, J. A., Gellespie, M. M., Llndtsen, T. and Thompson, C. B. (1987) T cell proliteration involving the CD 28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Molec. Cell. Biol., 7, 4472PubMedGoogle Scholar
  26. 26.
    Reed, J. C., Prystowsky, M. B. and Nowell, P. C. (1988) Regulation of gene expression in lectin-stimulated or lymphokine-sttimulated T lymphocytes. Transplantation, 26 (Suppl.), 85Google Scholar
  27. 27.
    Larsson, E. L. (1980) Cyclosporin A and dexmethansone suppress T cell responses by selectively acting at distinct sites of the triggering process. J. Immunol., 124, 2828PubMedGoogle Scholar
  28. 28.
    Wagner, H. (1983) Cyclosporine A: mechanism of action. Transplant. Proc., 15, 523Google Scholar
  29. 29.
    Hess, A. D. and Tutschka, P. J. (1980) Effects of cyclosporine A on human lymphocyte responses in vitro. I. CsA allows for the expression of alloantigen-activated suppressor cells whilep referentially inhibiting the induction of cytolytic effector lymphocytes in MLR. J. Immunol., 124, 2601PubMedGoogle Scholar
  30. 30.
    Heeg, K., Gillis, S. and Wagner, N. (1988) IL-4 bypassed the immune suppressive effect of Cyclosporin A during the in vitro induction of immune cytotoxic T lymphocytes. J. Immunol., 141, 2330PubMedGoogle Scholar
  31. 31.
    Wagner, H., Hardt, C., Rouse, B., Rollinghoff, M., Scheurich, P. and Pfizermaier, F. (1982) Dissection of the proliferative and differentiative signals controlling murine cytotoxic T lymphocyte responses. J. Exp. Med., 155, 1876PubMedCrossRefGoogle Scholar
  32. 32.
    Miyawaki, T., Yachie, A., Ohzeki, S., Nagoaki, T. and Taniguchi, N. (1983) Cyclosporin A does not prevent expression of TAC antigen, a probable TCGF receptor molecule on mitogen stimulated human T cells, J. Immunol., 130, 2737PubMedGoogle Scholar
  33. 33.
    Ryffel, B., Tammi, K., Greider, A. and Hess, A. D. (1985) Effects of cyclosporine on human T cell activation. Transplant Proc., 17, 1268Google Scholar
  34. 34.
    Hess, A. D., Donnenberg, A. D., Tutschka, P. J. and Santos, G. W. (1983) Effect of cyclosporin A on human lymphocyte responses in vitro. V. Analysis of responding T lymphocytes subpopuiation in primary MLR with monoclonal antibodies. J. Immunol., 130, 717PubMedGoogle Scholar
  35. 35.
    Lillehoj, H. S., Malek, T. R. and Shevach, E. M. (1984) Differential effect of cyclosporin A on the expression of T and B lymphocyte activation antigens. J. Immunol., 133, 244PubMedGoogle Scholar
  36. 36.
    White, D. J. G. (1982) Pharmacology of cyclosporin A. Drugs, 24, 322PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1989

Authors and Affiliations

  • Allan D. Hess

There are no affiliations available

Personalised recommendations