Abstract
The potential of cyclosporin A (CsA) for the immunotherapy of allograft rejection and certain autoimmune disorders was evident in the first account by Borel et al. (1976) of the immunosuppressive properties of the drug. It was clear from such early publications that CsA exerted a powerful and selective inhibitory action against T lymphocytes. Whilst the capacity of CsA to abrogate the activation of CD4+ (T helper/inducer) lymphocytes and the secretion of interleukin-2 (IL-2) and other cytokines in vitro is now well recognized, the molecular basis of this remarkably sophisticated selectivity remains to be elucidated. Although the generation of specific cytotoxic T cells is impaired by CsA, the activity of natural cytotoxic cells (NK cells) appears unaffected.
Chapter PDF
References
Ryffel, B., Götz, U. and Heuberger, B. (1982) Cyclosporin receptors on human lymphocytes. J. Immunol., 129, 1978
LeGrue, S. J., Friedman, A. W. and Kahan, B. D. (1983) Binding of cyclosporine by human lymphocytes and phospholipid vesicles, J. Immunol., 131, 712
Palacios, R. (1982) Mechanisms of T cell activation: role and functional relationship of HLA-DR antigens and interleukins. Immunol Rev., 63, 73
Ryffel B., Willard-Gallo, K. E., Tammi K. and Lokenr M. R. (1984) Quantitative fluorescence analysis of cyclosporine binding to human leukocytes. Transplantation, 37, 276
Russel D. H., Kibler, D. H., Matrison, L., Larson, D. P., Poulos, B. and Magun, B. E. (1985) Prolactin receptors on human T and B lymphocytes: antagonism of prolactin binding of cyclosporin. J. Immunol., 134, 3027
Heistand, P. C., Mekler, P., Nordmann, R., Glieder, A. and Permmongkol, C. (1986) Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action of CsA. Proc. Natl. Acad. Sci. USA, 83, 2599
Hess, A. D. and Colombani, P. N. (1988) Inverse correlation of cyclosprine binding with sensitivity and resistance. Transplantation, 46 (Suppl.), 61S
Rossaro, L., Dowd, S. R., Ho, C. and Van Thiel, D. H. (1988) 19F Nuclear magnetic resonance studies of cyclosporine and model unilamellar veiscles: where does the drug sit within the membrane? Transplant. Proc., 20 (Suppl. 2), 41
Szamel, M., Berger, P. and Resch, K. (1986) Inhibition of T lymphocyte activation by cyclosporin A: interference with the early activation of plasma membrane phospholipid metabolism. J. Immunol., 136, 264
Foxwell, B. M. J., Frazer, G., Winters, M., Heistand, P., Wenger, R. and Ryffel B. (1988) Identification of cyclophilin as the erythrocyte ciclosporin-binding protein. Biochim. Biophys. Ada, 938, 447
King, S. L. (1988) An assessment of phosphoinositide hydrolysis in antigenic signal transduction in lymphocytes. Immunology, 65, 1
Hess, A. D., Esa, A. and Colombani, P. M. (1988) Mechanisms of action of cyclosporine: effects on cells of the immune system and on subcellular events in T cell activation. Transplant. Proc., 20 (Suppl. 2), 29
Isakov, N., Scholz, W. and Altman, A. (1987) Effect of cyclosporine A on early stages of T cell activation. Transplant. Proc., 14, 1186
Manger, B., Hardy, K. J., Weiss, A. and Stobo, J. D. (1986) Differential effect of cyclosporin A on activation signalling in human T cell lines. J. Clin. Invest., 77, 1501
Isakov, N. and Altman, A. (1987) Human T lymphocyte activation by tumor promoters: role of protein kinase C. J. Immunol., 138, 3100
Gelfand, E. W., Cheung, R. K. and Mils, G. B. (1987) The cyclosporins inhibit lymphocyte activation at more than one site. J. Immunol., 138, 1115
Ryffel, B., Müller, S. and Foxwell, B. (1987) CsA allows the expression of high affinity IL-2 binding sites on anti-T cell antibody activated human T lymphocytes. Transplant. Proc., 19, 1199
Lillehoj, H. S., Malek, T. R. and Shevach, E. M. (1984) Differential effect of CsA on the expression of T and B lymphocyte activation antigens. J. Immunol., 133, 244
Prince, H. E. and John, J. K. (1986) Cyclosporin inhibits the expression of receptors for IL-2 and transferrin on mitogen-activated human T lymphocytes. Immunol. Invest., 15, 463
Redelman, D. (1988) Cyclosporin A does not inhibit the PHA-stinulated increase in intracellular Ca2+ concentration but inhibits the increase in E-rosette receptor (CD2) expression and appearance of interleukin-2 receptors (CD25). Cytometry, 9, 156
Granelli-Pipemo, A., Inaba, K. and Steinman, R. (1984) Stimulation of lymphokine release from T lymphoblasts-requirement for mRNA synthesis and inhibition by CsA. J. Exp. Med., 160, 1792
Hodgkin, P. D., Hapel, A. J., Johnson, R. M., Young, I. G. and Lafferty, K. J. (1987) Blocking of delivery of the antigen-mediated signal to the nucleus of T cells by cyclosporin. Transplantation, 43, 685
Noonan, D. J., Isakov, N., Theofilopoulos, A N., Dixon, F. J. and Altman, A. (1987) Protein kinase C-activating phorbol esters augment expression of T cell receptor genes. Eur. J. Immunol., 17, 803
Metcalfe, S. (1984) Cyclosporin does not prevent cytoplasmic calcium changes associated with lymphocyte activation. Transplantation, 38, 161
Wiskovil, R., Weiss, A., Imboden, J., Kamin-Lewis, R. and Stobo, J. (1985) Activation of a human T cell line: A two-stimulus requirement in the pretranslational events involved in the coordinate expression of interleukin 2 and γ-interferon genes. J. Immunol., 134, 1599
Colombani, P. M., Robb, A. and Hess, A. D. (1985) CsA binding to calmodulin: a possible site of action on T lymphocytes. Science, 228, 338
LeGrue, S. J., Turner, R., Weisbrodt, N. and Redman, J. R. (1986) Does the binding of cyclosporin to calmodulin result in immunosuppression? Science, 234, 68
Gschwendt, M., Kittstein, W. and Marks, F. (1988) The weak immunosuppressant cyclosporine D as well as the immunologically inactive cyclosporine H are potent inhibitors in vivo of phorbol ester TPA-induced biological effects in mouse skin and of Ca2+/calmodulin dependent EF-2 phosphorylation in vitro. Biochem. Biophys. Res. Commun., 150, 545
Handschumacher, R. E., Harding, M. W., Rice, J. and Drugge, R. J. (1984) Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science, 226, 544
Harding, M. W. and Handschumacher, R. E. (1988) Cyclophilin, a primary molecular target for cyclosporine. Transplantation, 46 (Suppl.), 29S
Durette, P. L., Boger, J., Dumont, F., Firestone, R., Frankshun, R. A., Koprak, S. L., Lin, C. S., Melino, M. R., Pessolano, A. A., Pisano, J., Schmidt, J. A., Sigal, N. H., Staruch, M. J. and Witzel, B. E. (1988) A study of the correlation between cyclophilin binding on in vitro immunosuppressive activity of cyclosporine A and analogues. Transplant. Proc., 20 (Suppl. 2), 51
Quesniaux, V. F. J., Schreier, M. H., Wenger, R. M., Hiestand, P. C., Harding, M. W. and Van Regenmortel, M. H. V. (1988) Molecular characteristics of cyclophilin-cyclosporin interaction. Transplantation, 46 (Suppl.), 23S
Hess, A. D. and Colombani, P. M. (1987) Mechariisms of action of cyclosporine: role of calmodulin, cyclophilin and other cyclosporin-binding proteins. Transplant. Proc., 18 (Suppl. 5), 219
Foxwell, B. M. J., Hiestand, P. C., Wenger, R. and Ryffel, B. (1988) A comparison of cyclosporine binding by cyclosporin-binding proteins. Transplant. Proc., 18 (Suppl.), 35S
Bunjes, D., Hardt, C, RöDinghoff, M. and Wagner, H. (1981) CsA mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of IL-1 and IL-2. Eur. J. Immunol., 11, 657
Andrus, L. and Lafferty, K. J. (1982) Inhibition of T cell activity by CsA. Scand. J. Immunol., 15, 449
Wagner, H. (1983) CsA: mechanism of action. Transplant. Proc., 15, 523
Granelli-Piperno, A., Keane, M. and Steinman, R. M (1988) Evidence that cyclosporine inhibits cell-mediated immunity primarily at the level of the T lymphocyte rattier than the accessory cell. Transplantation, 46, Suppl. 53S
Granelli-Piperno, A., Andrus, L. and Steinman, R. M. (1986) Lymphokine and non-lympholdne mRNA levels in stimulated human T cells. Kinetics, mitogen requirements and effects of CsA. J. Exp. Med., 163, 922
Hess, A. D., Tutschka, P. J. and Santos, G. W. (1982) Effect of CsA on human lymphocyte responses in vitro. III. CsA inhibits production of T cell growth factor in secondary MLC but does not inhibit response of primed lymphocytes to T cell growth factor. J. Immunol., 128, 355
Wang, B. S., Zheng, C., Heacock, G. H., Tllney, N. L., Strom, T. B. and Mannick, J. A. (1983) Inhibition of the production of a soluble helper mediator by CsA results in the failure to generate alloreactive cytolytic cells in MLC. Clin. Immunol Immunopathol., 27, 160
Dos Reiss, G. A. and Shevach, E. M. (1982) Effect of CsA on T cell function in vitro: the mechanism of suppression of T cell proliferation depends on the nature of the T cell stimulus as well as the differentiation state of the responding T cell. J. Immunol., 129, 2360
Kaufmann, Y., Chang, A. E., Robb, R. T. and Rosenberg, S. A. (1984) Mechanism of action of CsA: inhibition of lymphokine secretion studied with antigen-stimulated T cell hybridomas. J. Immunol., 133, 3107
Pawelec, G. and Wernet, P. (1983) CsA inhibits IL-2-dependent growth of alloactivated cloned human T cells, Int. J. immunopharmacol., 5, 315
Ferrini, S., Moretta, A., Biassoni, R., Nicolin, A. and Moetta, I. (1986) CsA inhibits IL-2 production by all human T cell clones having this function, independent of the T4/T8 phenotype or the co-expression of cytolytic activity. Clin. Immunol Immunopathol., 38, 79
Weiss, J., Schwinzer, B., Kirchner, H., Gemsa, D. and Resch, K. (1986) Effects of CsA on functions of specific murine TH cell clones: inhibition of proliferation, lymphokine secretion and cytotoxicity. Immunobiology, 171, 234
Heeg, K., Deusch, K., Solbach, W., Bunjes, D. and Wagner, H. (1984) Frequency analysis of cyclosporin-sensitive cytotoxic T lymphocyte precursors. Transplantation, 38, 532
Elliot, J. F., Lin, Y., Mizel, S. B., Bleackley, R. C., Hamish, D. G. and Paetkau, V. (1984) Induction of IL-2 mRNA inhibited by CsA. Science, 226, 1439
Reed, J. C., Prystowsky, M. B. and Nowell, P. C. (1988) Regulation of gene expression in lectin-stimulated or lymphokine-stimulated T lymphocytes. Transplantation, 46 (Suppl.), 75S
Orosz, C. G., Roopenian, D. C., Widmer, M. B. and Back, F. H. (1983) Analysis of cloned T cell function. II. Differential blockade of various cloned T cell functions by cyclosporin. Transplantation, 36, 706
Palacios, R. (1985) CsA inhibits antigen and lectin-induced but not constitutive production of IL-3. Eur. J. Immunol., 15, 204
Bickel, M., Tsuda, H., Amstad, P. et al. (1987) Differential regulation of colony-stimulating factors and interleukin 2 production by cyclosporin A. Proc. Natl. Acad. Sci. USA, 84, 3276
Shaw, J., Meerovitch, K., Elliot, J. F., Bleakley, R. C. and Paetkau, V. (1987) Induction, suppression and superinduction of lymphokine mRNA in T lymphocytes. Mol. Immunol., 24, 409
Sideras, P., Funa, K., Zalcberg-Qulntana, I., Xanthopoulos, K. G., Kislelow, P. and Palacios, R. (1988) Analysis by in situ hybridization of cells expressing mRNA for IL-4 in the developing thymus and in peripheral lymphocytes from mice. Proc. Natl. Acad. Sci. USA, 85, 218
Hu-Li, J., Shevach, E., Mizuguchi, J., Ohara, J., Mosmann, T. and Paul, W. (1987) B cell stimulatory factor 1 (interleukin 4) is a potent costimulant for normal resting T lymphocytes. J. Exp. Med., 165, 157
Gernandez-Botran, R., Krammer, P., Diamantstein, T., Uht J. and Vitetta, E. (1986) B cell-stimulatpry factor 1 (BSF-1) promotes growth of helper T cell lines. J. Exp. Med., 164, 580
Mathie, I. H., Sewell, H. F. and Thomson, A. W. (1987) Generation of large granular lymphocytes and subset changes linked with cyclophosphamide-irtduced eosinophilia in rats and the effects of ciclosporin. Scand. J. Immunol., 26, 417
Kalman, V. K. and Klknpel, G. R. (1983) CsA inhibits the production of gamma interferon (INFγ) but does not inhibit production of virus-induced IFNα/ß. Cell Immunol., 78, 122
Palacios, R., Martinez-Maza, O. and DeLey, M. (1983) Production of human gamma IFN studied at the single cell level: origin, evidence for spontaneous secretion and effects of CsA. Eur. J. Immunol., 13, 221
Reem, G. H., Cook, L. A. and Vilcek, J. (1983) Gamma IFN synthesis by human thymocytes and T lymphocytes inhibited by CsA. Science, 221, 63
Herold, K. C., Lancki, D. W., Moldwin, R. L. and Fitch, F. W. (1986) Immunosuppressive effects of CsA on cloned T cells. J. Immunol., 136, 1315
Liversidge, J., Sewell, H. F., Thomson, A. W. and Forrester, J. V. (1988) Lymphokine induced expression of MHC class II antigen expression on cultured retinal pigment epithelial cells and the influence of cyclosporin A. Immunology, 63, 313
Halloran, P. F., Urmson, J., Farkas, S., Phillips, R. A., Fulop, G., Cockfield, S. and Autenried, P. (1988) Effects of cyclosporine on systemic MHC expression. Evidence that non-T cells produce interferon-gamma in vivo and are inhibitable by cyclosporine. Transplantation, 46 (Suppl.), 68S
Espevik, T., Figari, I. S., Shalaby, M. F., Lackides, G. A., Lewis, G. D., Shepard, H. M. and Palladino, M. A. (1987) Inhibition of cytokine production by cyclosporin A and transforming growth factor ß. J. Exp. Med., 166, 571
Scheurich, P., Kronke, M., Schlüter, C., Ucer, U. and Pfizenmaier, K. (1986) Noncytocidal mechanisms of action of tumour necrosis factor-α on human tumour cells: enhancement of HLA gene expression synergistic with interferon-γ. Immunobiology, 172, 291
Thomson, A. W., Moon, D. K., Geczy, C. L. and Nelson, D. S. (1983) CsA inhibits lymphokine production but not the response of macrophages to lymphokines. Immunology, 48, 291
Thomson, A. W., Moon, D. K. and Nelson, D. S. (1983) Suppression of delayed type hypersensitivity reactions and lymphokine production by CsA in the mouse. Clin. Exp. Immunol., 52, 599
Helin, H. and Edgington, T. S. (1984) CsA regulates monocyte/macrophage effector functions by affecting instructor T cells: inhibition of monocyte procoagulant response to allogeneic stimulation. J. Immunol., 132, 1074
Larson, E-L. (1980) CsA and dexamethasone suppresses T cell responses by selectively acting at distinct sites of the triggering process. J. Immunol., 124, 2828
Miyawaki, T., Yachie, A., Ohzeki, S., Nagaoki, T and Taniguchi, N. (1983) CsA does not prevent expression of Tac antigen, a probable T cell growth factor receptor molecule on mitogen-stimulated human T cells. J. Immunol., 130, 2737
Kronke, M., Leonard, W. J., Depper, J. M., Arya, S. K., Wong-Stall, F., Gallo, R. C., Waldmann, T. A. and Greene, W. C. (1984) CsA inhibits T cell growth factor gene expression at the level of mRNA transcription. Proc. Natl Acad. Sci. USA, 81, 5124
Bloemena, E., van Oers, M. H. J., Weinreich, S., Yong, S-L. and Schellekens, P. T. A. (1988) Cyclosporine A does not prevent expression of biologically active IL-2 receptors in vitro. Transplant. Proc., 20(2), Suppl. 2, 131
Aiello, F. B., Maggiano, N., Larocca, L. M., Piantelli, M. and Musiani, P. (1986). Inhibitory effect of CsA on the OKT3-induced PBL proliferation. Cell Immunol, 97, 131
Gauchat, J.-F., Khandjian, E. W., Nabholz, M. and Weil, R. (1986) Cyclosporin A ‘seems’ to exert its immunosuppressive action primarily by preventing the activation of a set(s) of T lymphocyte-specific genes. Proc. Natl. Acad. Sci. USA, 83, 6430
Reed, J. C., Abldl, A. H., Alpers, J. D., Hoover, R. G., Robb, R. J. and Noweli P. C. (1986) Effect of cyclosporin A and dexamethasone on interleukin-2 receptor gene expression. J. Immunol., 137, 150
Smith, K. A. and Cantrell D. A. (1985). Interleukin-2 regulates its own receptors. Proc. Natl. Acad. Sci. USA, 82, 864
Harel-Bellan, A., Bertoglio, J., Quillet A., Marchiol, C., Wakasugi, H., MishalL Z. and Fradetizi, D. (1986) Interleukin 2 (IL-2) up-regulales its own receptor on a subset of human unprimed peripheral blood lymphocytes and triggers their proliferation. J. Immunol., 136, 2463
Kondo, S., Shimizu, A., Saito, Y., Kinoshita, M. and Honjo, T. (1986) Molecular basis for two different affinity states of the interleukin 2 receptor: affinity con version model. Proc. Natl. Acad. Sci. USA, 83, 9026
White, D. J. G., Plumb, A. M., Pawelec, G. and Brons, G. (1979) Cyclosporin A: an immunosuppressive agent preferentially active against proliferating T cells. Transplantation, 27, 55
Mcintosh, L. C. and Thomson, A. W. (1980) Activity of mononuclear phagocytes in CsA-treated mice. Transplantation, 30, 384
Alberti, S., Boeraschi, D., Luini, W. and Tagliabue, A. (1981) Effects of in vivo treatments with CsA on mouse cell-mediated immune responses. Int. J. Immunopharmacol., 3, 357
Manca, F., Kunkl, A. and Ceiada, F. (1985) Inhibition of the accessory function of murine macrophages in vitro by cyclosporine. Transplantation, 39, 644
Paley, D. A., Cluff, C. W., Wentworth, P. A. and Ziegler, H. K. (1986) CsA inhibits macrophage-mediated antigen presentation. J. Immunol., 136, 4348
Varey, A., Champion, B. R. and Cooke, A. (1986) Cyclosporine affects the function of APC. Immunology, 57, 111
Esa, A. H., Converse, P. J. and Hess, A. D. (1987) Cyclosporine inhibits soluble antigen and alloantigen presentation by human monocytes in vitro. Int. J. Immunopharmacol., 9, 893
Snyder, D. S., Wright, C. L. and Ting, C. (1987) Inhibition of human monocyte antigen presentation, but not HLA-DR expression, by cyclosporine. Transplantation, 44, 407
Manca, F., Fenoglio, D., Kunkl, A., Caltabellotta, M. and Ceiada, F. (1988) Effect of cyclosporine on the antigen-presenting function of human and murine accessory cells. Transplantation, 46 (Suppl.), 40S
Whisler, R. L., Lindsey, J. A., Proctor, K. V. W., Newhouse, Y. G. and Cornwell, D. G. (1985) The impaired ability of human monocytes to stimulate autologous and allogeneic MLC after exposure to cyclosporine. Transplantation, 40, 57
Uyemura, K., Dixon, J. F. P. and Parker, J. W. (1983) Inhibitory effect of cyclosporine on adherent cells in oxidation-induced lymphocyte proliferation. Transplant. Proc., 15, 2376
Uyemura, K., Dixon, J. F. P. and Parker, J. W. (1985) Cyclosporine inhibits macrophage accessory cell function in mitogen-induced lymphocyte proliferation. Transplant. Proc., 17, 1374
Esa, A. H., Paxman, D. G., Noga, S. J. and Hess, A. D. (1988) Sensitivity of monocyte subpopulations to cyclosporine arachldonate metabolism and in vitro antigen presentation. Transplant. Soc., 20 (Suppl. 2), 80
Knight, S. C., Balfour, B. M., O’Brien, J. and Buttifant, L. (1987) Sensitivity of veiled (dendritic) cells to cyclosporine. Transplantation, 41, 96
Knight, S. C. and Bedford, P. A. (1987) Effect of cyclosporine and retinoic acid on dendritic cell function. Transplant Proc., 19, 320
Furue, M. and Katz, S. I. (1988) Cyclosporine A inhibits accessory cell and antigen-presenting cell functions of epidermal Langerhans cells. Transplant. Proc., 20 (Suppl. 2), 87
Muller, S., Adorini, L., Appella, E. and Nagy, Z. A. (1988) Lack of influence of cyclosporine on antigen presentation to lysozyme-specifk T cell hybridomas. Transplantation, 46 (Suppl), 44S
Cox, J. H. and Chisholm, P. M. (1987) Mechanism of action of cyclosporin in preventing cardiac allograft rejection. I. Rate of entry of lymphocytes from the blood, fibrin deposition and expression of la antigens on infiltrating cells. Transplantation, 43, 338
Halloran, P. F., Wadgymar, A and Autenried, P. (1986) Inhibition of MHC product induction may contribute to the immunosuppressive action of ciclosporin. Progr. Allergy, 38, 258
Groenewegen, W. A., Buurman, W. A. and Jeunhomme, G. M. A. A. (1985) Class II expression of endothelial cells is affected by cyclosporins Transplant Proc., 17, 1417
Groenewegen, G., Buurman, W. A., Jeunhomme, G. M. A. A. and Linden, G. J. van der (1985) Effect of cyclosporin on MHC class II antigen expression on arterial and venous endothelium in vitro. Transplantation, 40, 21
Orosz, C. G., Adams, P. W. and Ferguson, R. M. (1988) Frequency of human alloantigen-reactive T lymphocytes. III. Evidence that cyclosporine has an inhibitory effect on human CTL and CTL precursors, independent of CsA-rnedlated helper T cell dysfunction. Transplantation, 46 (Suppl.), 73S
Shevach, E. M. (1985) The effects of CsA on the immune system, Ann. Rev. Immunol., 3, 397
Hess, A. D. and Colornbani, P. M. (1986) Mechanisms of action: in vitro studies. Progr. Allergy, 38, 198
Thomson, A. W., Whiting, P. H., Blair, J. T., Davidson, R. J. L. and Simpson, J. G. (1981) Pathological changes developing in the rat during a three week course of high dose cyclosporin A and their reversal following drug withdrawal. Transplantation, 32, 271
Blair, J. T., Thomson, A. W., Whiting, P. H., Davidson, R. J. L. and Simpson, J. G. (1982) Toxicity of the immune suppressant cyclosporin A in the rat. J. Pathol., 138, 163
Demitris, A. J., Nalesnik, M. A., Kunz, H. W., Gill, T. J. and Shinozuka, H. (1984). Sequential analysis of the development of lymphoproliferative disorders in rats receiving cyclosporins. Transplantation, 38, 239
Beschorner, W. E., Di Gennaro, K. A., Hess, A. D. and Santos, G. W. (1987) Cyclosporine and the thymus: influence of irradiation and age on thymic immunopathology and recovery. Cell Immunol., 110, 350
Beschorner, W. E., Namnoum, J. D. and Hess, A. D. (1987) Immunopalhology of rat thymus after cyclosporin A. Transplant. Proc., 19, 1230
Baldwin, W. M., Hutchison, I. F., Maijer, C J. L. M. and Tilney, N. L. (1981) Immune responses to organ allografts. III. Marked decrease in medullary thymocytes and splenic T lymphocytes after cyclosporin A treatment. Transplantation, 31, 117
Calne, R. Y., White, D. J. G., Evans, D. B., Thiru, S., Henderson, R. G., Hamilton, D. V., Rolles, K., McMaster, R., Duffy, T. J., MacDougali, B. R. D. and Williams, R. (1981) Cyclosporin A in cadaveric organ transplantation. Br. Med. J., 282, 934
Hutchison, I. F., Shadur, C. A., Duarfe, J. S. A., Strom, T. B. and Tilney, N. L. (1981) Cyclosporin A spares selectively lymphocytes with donor-specific suppressor characteristics. Transplantation, 32, 210
Bordes-Aznar, J., Kupiec-Weglinski, J. W., Duarte, A. J. S. (1983) Function and migration of suppressor lymphocytes from cyclosporin-treated heterograft recipients. Transplantation, 35, 185
Kupiec-Weglinski, J. W., Lear, P. A., Bordes-Aznar, J., Tilney, N. L. and Strom, T. B. (1983) Acute rejection in cyclosporin A-treated graft recipients occurs following abrogation of suppressor cells. Transplant Proc., 15, 531
Kuromoto, N., Iga, C., Fawwaz, R., Nowygrod, R., Reemstma, K. and Hardy, M. A. (1983) Effect of cyclosporin on lymphocyte migration in rat cardiac transplantation. Transplant. Proc., 15, 2973
Glazier, A., Tutchka, P. J., Farmer, E. R. and Santos, G. W. (1983) Graft-versus-host disease in cyclosporin A-treated rats after syngeneic and autologous bone marrow reconstitution. J. Exp. Med., 158, 1
Sweny, P. and Tidman, N. (1982) The effect of cyclosporin A on peripheral blood T cell subpopulations in renal allografts. Clin. Exp. Immunol., 47, 445
Nussenblatt, R. B., Hoak, A. H., Wacker, W. B., Palestine, A. G., Schir, I. and Gery, I. (1983) Treatment of intraocular inflammatory disease with cyclosporin A. Lancet, 2, 235
Assan, R., Derray-Sachs, M, Laboie, C., Chatenoud, L., Feutren, G., Quiniou-Debrie, M. C., Thomas, B. and Bach, J. F. (1985) Metabolic and immunological effects of cyclosporin in recently diagnosed type 1 diabetes mellitus. Lancet, 1, 67
Kerman, R. H., Flechner, S. M., van Buren, C. T., Lorber, M. I. and Kahan, B. D. (1987) Role of suppressor cells in cyclosporin-treated allograft recipients. Transplant. Proc., 19, 1580
Henny, R. L., Weening, J. L., Baldwin, W. M., Olsans, P. J., Tanke, H. J., Vanes, L. A. and Paul, L. C (1986) Expression of HLA-DR antigens on peripheral blood T lymphocytes and renal graft tubular epithelial cells in association with rejection. Transplantation, 42, 479
Morris, P. J., Carter, N. P., Cullen, P. R., Thompson, J. F. and Wood, R. F. M. (1982) Role of T-cell-subset monitoring in renal allograft recipients. N. Engl. J. Med., 306, 1110
Daniel, U., Opelz, G. and Dreihorn, K. (1985) Lymphocyte subpopulations in kidney transplant patients with différent types of immunosuppression. Transplant. Proc., 17,2554
Birkeland, S. A. (1985) Immunological monitoring of renal transplant patients treated with prednisolone/azathioprine or cyclosporine A. Transplant. Proc., 17, 2543
Van der Heyden, A. A. P. A. M., van Oers, M. H. J., Cornelissen, P., Yong, S-L., Wilmink, J. M. and Schellekens, P. T. A. (1988) The influence of cyclosporin A treatment on immune responsiveness in vitro and in vivo in kidney transplant recipients. Transplant. Proc., 20 (Suppl. 2), 190
DuPont, E, Huygen, K., Schandene, L., Vandercruys, M., Palfliet, K. and Wybran, J. (1985) Influence of in vivo immunosuppressive drugs on production of lymphokines. Transplantation, 39, 143
Yoshimura, N., Oka, T., Ohmori, Y., Aikawa, I., Fukuda, M. and Kahan, B. D. (1987) Influence of in vivo cyclosporin on interleukin production in kidney transplant recipients. Transplant. Proc., 19, 1193
Abbud-filho, M. (1984) Unpublished data; cited by Kupiec-Weglinski, J. W. et al.180. Transplantation, 133, 2582
Flechner, S. M., Kerman, R. H., Van Buren, G. T., Epps, L. and Kahan, B. D. (1984) The use of cyclosporine in living-related renal transplantation. Donor specific hyporesponsive-ness and steroid withdrawal. Transplantatton, 38, 685
Keown, P. A., Essery-Rice, G., Hellstrom, A., Sinclair, N. R. and Stiller, C. R. (1985) Inhibition of human in vivo cytotoxic T lymphocyte generation by cyclosporine following organ transplantation. Transplantation, 40, 45
Kerman, R. H. (1988) Effects of cyclosporine immunosuppression in humans. Transplant. Proc., 20 (Suppl. 2), 143
Borel, J. F., Feurer, C., Magnee, C. and Staheiin, H. (1977) Effects of the new antilymphocytic peptide CsA in animals. Immunology, 32, 1017
Thomson, A. W. and Aldridge, R. D. (1984) Absence of dependence on cyclophosphamide-sensitive suppressor cells in suppression of cell-mediated immunity by CsA in the guinea pig. Transplantation, 38, 76
Dunn, C. J. and Miller, S. K. (1986) The effects of CsA on leukocyte infilration and procoagulant activity in the mouse DTH response in vivo. Int. J. Immunopharmacol., 8, 635
Shidani, B., Milon, G., Marchai, G. and Truffa-Bachi, P. (1984) CsA inhibits the DTH reaction: impaired production of early pro-Inflammatory mediators. Eur. J. Immunol., 14, 314
Mottram, P. L., Mirisklavos, A., Dumble, L. J. and Clunie, G. J. A. (1986) Effects of CsA, antilymphocyte serum, and donor-specific transfusions on murine DTH and skin graft survival. Int. Arch. Allergy Appl. Immunol, 79, 296
Xue, B., Dersarkissian, R. M., Baer, R. L., Thorbecke, G. J. and Belsito, D. V. (1986) Reversal by lymphokines of the effect of cyclosporin A on contact sensitivity and antibody production in mice. J. Immunol., 11, 4128
Woo, J. and Thomson, A. W. (1989) Alleviation of cyclosporin-induced immune suppression by the cytokine inducer ADA-202–718. Immunopharmacology (In press)
Webster, L. M. and Thomson, A. W. (1987) Cyclosporin A prevents suppression of delayed-type hypersensitivity in mice immunized with high dose sheep erythrocytes. Immunology, 60, 409
Webster, L. M. and Thomson, A W. (1988) Augmentation of delayed-type hypersensitivity to high dose sheep erythrocytes by cyclosporin A in the mouse: influence of drug dosage and route of administration and analysis of spleen cell populations. Clin. Exp. Immunol., 71, 149
Aldridge, R. D. and Thomson, A. W. (1986) Paradoxical augmentation of tuberculin-like hypersensitivity but not Jones-Mote or contact sensitivity in CsA-treated guinea pigs. Int. Arch. Allergy Appl. Immunol., 79, 225
Aldridge, R. D. and Thomson, A. W. (1986) Factors Influencing the enhancement of DTH to ovalbumin by CsA in the guinea pig: possible role of suppressor cells. Int. Arch. Allergy Appl. Immunol., 81, 17
Altmann, D. M. and Blythr W. A. (1985) The effects of CsA on the induction, expression and regulation of the immune response to Herpes Simplex virus. Clin. Exp. Immunol., 59, 17
Braida, M. and Knop, J. (1986) Effect of CsA on the T effector and T suppressor cell response in contact sensitivity. Immunology,59, 503
Aldridge, R. D., Thomson, A. W., Rankin, R., Whiting, P. H., Cunningham, C. and Simpson, J. G. (1985) Inhibition of contact sensitivity reactions to DNFB by topical cyclosporin application in the guinea pig. Clin. Exp. Immunol., 59, 23
Aldridge, R. D., Sewell H. F., King, G. and Thomson, A. W. (1986) Topical cyclosporin A in nickel contact hypersensitivity: results of a preliminary clinical and immunohistochemical investigation. Clin. Exp. Immunol., 66, 582
Payne, S. N. L. and Thomson, A. W. (1989) Immunohistochemical analysis of contact sensitivity reactions in the guinea pig using novel monoclonal antibodies: the influence of topical cyclosporin A. Clin. Exp. Immunol. (In press)
Knight, S. C., Roberts, M., Macatonia, S. E. and Edwards, A. J. (1988) Blocking of acquisition and presentation of antigen by dendritic cells with cyclosporine. Studies with fluorescein isothiocyanate. Transplantation, 46 (Suppl.), 48S
Thomson, A. W., Milton, J. I., Aldridge, R. D., Davidson, R. J. L and Simpson, J. G. (1986) Inhibition of drug-induced eosinophilia by cyclosporin A. Scand. J. Immunol., 24,163
Cummins, A. G., Munro, G. H. and Ferguson, A. (1988) Effect of cyclosporin A on rat mucosal mast cells and the associated protease MCPII. Clin. Exp. Immunol., 72, 136
Klaus, G. G. B. and Chisholm, P. M. (1986) Does cyclosporine act in vivo as it does in vitro? Immunol Today, 7, 101
Thomson, A. W. (1987) Immunobiology of cyclosporin A, with particular reference to its effects on delayed hypersensitivity and regulatory T-cell functions. Ann. Inst. Pasteur/Immunol., 138, 639
Morris, P. J. (1981) Cyclosporin A. Transplantation, 32, 349
Land, W., Castro, L. A., White, D. J. G., Hillebrand, G., Hammer, C., Klare, B. and Fornara, P. (1986) Ciclosporin in renal transplantation. Progr. Allergy, 38, 293
Kaibara, N., Hotokebuchi, T., Takagishi, K. and Katsuki, I. (1983) Paradoxical effects of cyclosporin A on collagen arthritis in rats. J. Exp. Med., 158, 2007
Sorokin, R., Kimura, H., Schroder, K., Wilson, D. H. and Wilson, D. B. (1986) Cyclosporin-induced autoimmunity: conditions for expressing disease, requirements for intact thymus and potency estimates of autoimmune lymphocytes in drug-treated rats. J. Exp. Med., 164, 1615
Chisholm, P. M., Drayson, M. T., Cox, J. H. and Ford, W. L. (1985) the effects of cyclosporin on lymphocyte activation in a systemic graft-versus-host reaction. Eur. J. Immunol., 15, 1054
Chisholm, P. M. and Bevan, D. J. (1988) T cell activation in the presence of cyclosporine in three in vivo allograft models. Transplantation, 46 (Suppl.), 80S
Kroczek, R. A., Black, C. D. V., Barbet, J. and Schevach, E. M. (1987) Mechanism of action of cyclosporin A in vivo. I. Cyclosporin A fails to inhibit T lymphocyte activation in response to alloantigens. J. Immunol., 139, 3597
Milon, G., Truffa-Bachi, P., Shidani, B. and Marchai, G. (1984) CsA inhibits the DTH effector function of T lymphocytes without affecting their clonal expansion. Ann. Inst. Pasteur, Immunol., 135D, 237
Schiltknecht, E. and Ada, G. L. (1985) The generation of effector T cells in influenza-infected, cyclosporin A-treated mice. Cell Immunol., 95, 340
Severinson, E., Naito, T., Tokumoto, H., Fukushima, D., Hirano, A., Hama, K. and Honjo, T. (1987) Interieukin 4 (IgG1 induction factor): a multifunctional lymphokine acting also on T cells. Eur. J. Immunol., 17, 67
Widmer, M. M. and Grabstein, K. H. (1987) Regulation of cytolytic T-lymphocyte generation by B-cell stimulatory factor. Nature, 326, 795
Heeg, K., Gillis, S. and Wagner, H. (1988) IL-4 bypasses the immune suppressive effect of cyclosporin A during the in vitro induction of murine cytotoxic T lymphocytes. J. Immunol., 141, 2330
Freed, B. M., Stevens, C., Zhang, G., Rosano, T. F. and Lempert, N. (1988) A comparison of the effects of cyclosporine and steroids on human T lymphocyte responses. Transplant. Proc., 20 (Suppl. 2), 233
Hess, A. D., Horwitz, L., Beschomer, W. E. and Santos, G. W. (1985) Development of graft-vs-host disease-like syndrome In cyclosporine-treated rats after syngeneic bone marrow transplantation. J. Exp. Med., 161, 718
Lafferty, K. J., Gill, R. and Babcock, S. (1986) Tolerance induction in adult animals. The cicloporin anomaly. Progr. Allergy, 38, 247
Beschorner, W. E., Shinn, C. A., Fischer, A. C., Santos, G. W. and Hess, A. D. (1988) Cyciosporine-induced pseudo-graft-versus-host disease in the early post cyclosporine period. Transplantation, 46 (Suppl.), 112S
Ryffel, B., Deyssenroth, H. and Borel, J. F. (1981) Cyclosporin A: effects on the mouse thymus. Agents Actions, 11, 373
Xi-En, G. U. I., Rinaldo, C. R. and Monro, H. O. (1983) NK cell activity in renal transplant recipients receiving cyclosporin. Infect. Immun., 41, 965
Versluis, D. J., Melselaar, H. J., Bijma, A. M., Vaessen, L. M. B., Wenting, G. J. and Weimar, W. (1988) The effect of long-term cyclosporine therapy on natural killer cell activity. Transplant. Proc., 20 (Suppl. 2), 179
Shao-Hsien, C., Lang, I., Gurm, H. and Lydyard, P. (1983) Effect of in vitro CsA treatment on human natural and antibody-dependent cell-mediated cytotoxicity. Transplantation, 35, 127
Introna, M., Allavena, P., Spreafico, F. and Mantovani, A. (1981) Inhibition of human NK activity by CsA. Transplantation, 31, 113
Peterson, P. K., Rynasiewicz, J. J., Simmons, R. L. et al. (1983) Decreased incidence of overt cytomegalovirus disease in renal allografted recipients receiving cyclosporin A. Transplant. Proc., 15, 457
Cauda, R., Citierio, F., Tamborrini, E., Pozzerio, U., Tumbarelio, M., Castagneto, M. and Ortona, L. (1988) Natural killer activity against targets In cyclosporine-treated renal allograft recipients. Transplant. Proc., 20 (Suppl. 2), 186
Stewart, L. S., Sewell, H. F. and Thomson, A. W. (1989) Failure of cyclosporine A to affect generation of large granular lymphocytes (OX-8+, OX-19–) and natural killer cell activity following systemic cyclophosphamide administration and immunization in the rat. Transplant. Proc. (In press).
Tellides, G., Dallman, M. J. and Morris, P. J. (1988) Synergistic interaction of cyclosporine A with interleukin 2 receptor monoclonal antibody therapy. Transplant. Proc., 20 (Suppl. 2), 202
Kupiec-Weglinski, J. W., Hahn, H. J., Kirkman, R. L., Volk, H. D., Mouzaki, A., Di Stefano, R., Tellides, G., Dallman, M., Morris, P. J., Strom, T. B., Tilney, N. L. and Diamantstein, T. (1988) Cyclosporine potentiates the immunosuppressive effects of anti-interleukin 2 receptor monoclonal antibody therapy. Transplant. Proc., 20 (Suppl. 2), 207
Hahn, H. J., Kuttler, B., Dunger, A., Klöting, I., Lucke, S., Volk, H. D., Baehr, R. V. and Diamantstein, T. (1987) Prolongation of rat pancreatic islet allograft survival by treatment of recipient rats with monoclonal anti-interleukin-2 receptor antibody and cyclosporin. Diabetologia, 30, 44
Kupiec-Weglinski, J. W., Filho, M. A., Strom, T. B. and Tilney, N. L. (1984) Sparing of suppressor cells: a critical action of cyclosporine. Transplantation, 38, 97
Kupiec-Weglinski, J. W., Diamantstein, T., Tilney, N. L. et al. (1986) Therapy with monoclonal antibody to interleukin 2 receptor spares suppressor T cells and prevents or reverses acute allograft rejection in rats. Proc. Natl. Acad. Sci. USA, 83, 2624
Kupiec-Weglinski, J. W., Padberg, W., Uhteg, L. C., Ma, L., Lord, R. H., Araneda, D., Strom, T. B., Diamantstein, T. and Tilney, N. L. (1987) Selective immunosuppression with anti-interleukin 2 receptor-targeted therapy: helper and suppressor cell activity in rat recipients of cardiac allografts. Eur. J. Immunol., 17, 313
Thomson, A. W. (1989) FK-506. How much potential? Immunol. Today, 10, 6
Zeevi, A., Duquesnoy, R., Eiras, G., Rabinwich, H., Todo, S., Makowka, L. and Starzl, T. E. (1987) Immunosuppressive effect of FK-506 on in vitro lymphocyte alloactivation: synergism with cyclosporine A. Transplant. Proc., 19 (Suppl. 6), 40
Murase, N., Todo, S., Lee, P-H. et al. (1987) Heterotopic heart transplantation in the rat receiving FK-506 alone or with cyclosporine. Transplant. Proc., 19 (Suppl. 6), 71
Stephen, M. E., Woo, J., Hasan, N. U., Whiting, P. H. and Thomson, A. W. (1989) Immunosuppressive activity, lymphocyte subset analysis and acute toxicity of FK-506 in the rat: a comparative and combination study with cyclosporins Transplantation, 47, 60
Storb, R., Deeg, H. J., Whitehead, J., Appelbaum, F., Beattyr P., Besinger, W., Buckner, C. D., Clift, R., Doney, K., Farewell V., Hansen, J., Hill R., Wlfherspoon, R., Yee, G., Thomas, E. D. (1986) Methotrexate and cyclosporine compared with cydosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N. Engl. J. Med., 314, 729
Rynasiewicz, J. J., Sutherland, D. E. R., Ferguson, R. M., Squifflet, J. A., Morrow, C. E., Goetz, F. C. and Najarian, J. S. (1988) Cydosporin A for immunosuppression: observations in rat heart, pancreas and islet allograft models and in human renal and pancreas transplantation. Diabetes, 31 (Suppl. 4), 92
Squifflet, J. P., Sutherland, D. E. R., Rynasiewicz, J. J., Field, J., Heil, J. and Najarian, J. S. (1989) Combined immunosuppressive therapy with cyclosporin A and azathioprine. A synergistic effect in three of four experimental models. Transplantation, 34, 315
Aeder, M. I., Lews, W. I., Sutherland, D. E. R. et al. (1985) Combination immunotherapy for prolongation of renal allograft survival Transplant. Proc., 17, 2675
Collier, D. St. J., Thick, M., Curtins, M. D., White, D. J. G., Caine, R. Y., Jamieson, N. V., Barroso, E. and Thiru, S. (1986) Alternate-day immunosuppression. Lancet, 1, 267
Yen, C. Y., Greenstein, S. M., Lipkowitz, G. S., Hong, J. H., Nitta, K., Friedman, E. A. and Butt, K. M. H. (1987) Daily and alternate day cyclosporine immunosuppressive regimens and synergism with azathioprine. Transplant. Proc., 19, 1272
Brady, H. R., Peters, P. and Cardella, C. J. (1988) Synergistic effects of cyclosporine and rabbit antilymphocyte sera on suppression of the one-way allogeneic mixed lymphocyte response. Transplant. Proc., 20 (Suppl. 2), 229
Gordon, D. and Nouri, A. M. E. (1981) Comparison of the inhibition by glucocorticosteroids and cyclosporin A of mitogen-stirnutlated human lymphocyte proliferation. Clin. Exp. Immunol., 44, 287
Freed, B. M., Stevens, C., Zhang, G., Rosano, T. G. and Lempert, N. (1988) A comparison of the effects of cyclosporine and steroids on human T lymphocyte responses. Transplant. Proc., 20 (Suppl. 2), 253
Vogelsang, G. B., Wells, M. C., Santos, G. W., Chen, T. L and Hess, A. D. (1988) Combination low dose thalidomide and cyclosporine prophylaxis for acute graft-versus-host disease in a rat mismatched model. Transplant. Proc., 20 (Suppl. 2), 226
McMillen, M. A., Tesi, R. J., Baumgarten, W. B., Jaffe, B. M. and Wait, R. B. (1985) Potentiation of cyclosporine by varapamil in vitro. Transplantation, 40, 444
Weir, M. R., Peppier, R., Gomolka, D. and Handwerger, B. S. (1988) Additive effect of cydosporine and verapamil on the inhibition of activation and function of human peripheral blood mononudear cells. Transplant. Proc., 20 (Suppl. 2), 240
van Eendenburg, J. P., Brisson, E., Klatzmann, D. and Gluckman, J-C. (1988) Nicardipine enhances the effect of cyclosporine A on T lymphocyte activation in vitro. Transplant. Proc., 20 (Suppl. 2), 245
Rosano, T. G., Freed, B. M., Cerilli, J. and Lempert, N. (1986) Immunosuppressive metabolites of cydosporine in the blood of renal allograft recipients. Transplantation, 42, 262
Freed, B. M., Rosano, T. G. and Lempert, N. (1987) In vitro immunosuppressive properties of cyclosporin metabolites. Transplantation, 43, 123
Zeevi, A., Eiras, G., Burckart, G., Makowka, L., Venkataramanan, R., Wang, C. P., Van Thiel, D. H., Murase, N., Starzl, T. E. and Duquesnoy, R. (1988) Immunosuppressive effect of cyclosporine metabolites from human bile on alloreactive T cells. Transplant. Proc., 20 (Suppl. 2), 115
Zeevi, A., Venkataramanan, R., Burckart, G., Wang, C. P., Nurase, N., Van Thiel, D. H., Starzl, T. E., Makowka, L. and Duquesnoy, R. J. (1988) Sensitivity of activated human lymphocytes to cyclosporine and its metabolites. Human Immunol., 21, 143
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1989 Kluwer Academic Publishers
About this chapter
Cite this chapter
Thomson, A.W., Duncan, J.I. (1989). The influence of cyclosporin A on T cell activation, cytokine gene expression and cell-mediated immunity. In: Thomson, A.W. (eds) Cyclosporin. Springer, Dordrecht. https://doi.org/10.1007/978-94-009-0859-8_4
Download citation
DOI: https://doi.org/10.1007/978-94-009-0859-8_4
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-010-6874-1
Online ISBN: 978-94-009-0859-8
eBook Packages: Springer Book Archive