Effect of cyclosporin A on the immune response: pivotal role of the interleukin-2/ interleukin-2 receptor autocrine pathway
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.
KeywordsGraft Rejection Lymphokine Production Clonal Amplification Potent Immunosuppressive Activity Alloantigen Stimulation
Unable to display preview. Download preview PDF.
- 4.Schindler, R. (ed.) (1985) Ciclosporin in Autoimmune Diseases (Berlin: Springer-Verlag)Google Scholar
- 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
- 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.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
- 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
- 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
- 24.Citterio, F. and Kahan, B. P. (1988) Effects of cyclosporine on nuclear function. Trans. Proc., 20 (Suppl. 2), 75Google Scholar
- 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
- 28.Wagner, H. (1983) Cyclosporine A: mechanism of action. Transplant. Proc., 15, 523Google Scholar
- 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
- 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