Agents and Actions

, Volume 15, Issue 3–4, pp 306–327 | Cite as

Cyclosporine: Immunology, toxicity and pharmacology in experimental animals

  • A. W. Thomson
  • P. H. Whiting
  • J. G. Simpson
Immunosuppression and Inflammation Review


Cyclosporine (CsA) is the first of a new order of pharmacological immune suppressants and represents a significant advance in the clinical control of graft rejection. In laboratory animals, its capacity to prolong allograft survival has been well documented, including reports of indefinite donor-specific immunological tolerance after shortterm CsA treatment. There is also evidence that CsA can inhibit the onset or progress of a variety of experimental autoimmune diseases. Underlying these properties of the drug is its capacity to selectively interfere with T helper cell activation and lymphokine production, although some direct effects on B cells have also been reported. In addition, sparing of suppressor cells may in part explain the mode of action of CsA which, at the molecular level, is not understood.

CsA-induced nephrotoxicity in the rat has been extensively studied and is characterized by reversible proximal tubular cell damage. This problem may be aggravated by concomitant administration of other potentially nephrotoxic drugs, such as gentamicin, or by therapeutic agents which interfere with the metabolism of CsA.

CsA is metabolized in the liver and excreted in the bile. Although the pathway of hepatic metabolism of CsA has not been precisely elucidated, animal studies suggest that agents capable of inducing metabolism of the drug CsA could be used to alleviate its nephrotoxic properties.


Cyclosporine Gentamicin Graft Rejection Suppressor Cell Concomitant Administration 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    S. Alberti, D. Boraschi, W. Luini andA. Tagliabue,Effects of in vivo treatments with cyclosporin A on mouse cell-mediated immune responses, Int. J. Immunopharmacol.3, 357–364 (1981).Google Scholar
  2. [2]
    P. Alexander, Cyclosporin A and the growth, dissemination and induction of tumours. InCyclosporin A, pp. 299–305 (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  3. [3]
    L. Andrus andK.J. Lafferty,Inhibition of T cell activity by cyclosporin A, Scand. J. Immunol.15, 449–458 (1982).Google Scholar
  4. [4]
    D. Armerding, M. Scriba, A. Hren andH. Rossiter,Modulation by cyclosporin A of murine natural resistance against herpes simplex virus infection. I. Interference with the susceptibility to herpes simplex virus infection, Antiviral Research2, 3–11 (1982).Google Scholar
  5. [5]
    D. Armerding, M. Scriba, H. Kirchner, A. Hren andH. Rossiter,Modulation by cyclosporin A of murine natural resistance against herpes simplex virus infection. II. Influence on the HSV-induced natural killer cell responses, macrophage activities and interferon levels, Antiviral Research2, 13–26 (1982).Google Scholar
  6. [6]
    W.M. Baldwin, I.F. Hutchinson, C.J.L.M. Meijer andN.L. Tilney,Immune responses to organ allografts. III. Marked decrease in medullary thymocytes and splenic T lymphocytes after cyclosporin A treatment, Transplantation31, 117–120 (1981).Google Scholar
  7. [7]
    C.R. Baxter, G.G. Duggin, N.S. Willis, B.M. Hall, J.S. Horvath andD.J. Tiller,Cyclosporin A-induced increases in renin storage and release, Res. Comm. Chem. Pathol. Pharmacol.37, 305–311 (1982).Google Scholar
  8. [8]
    T.A.G. Bell, D.L. Easty andK.G. McCullagh,A placebo-controlled blind trial of cyclosporin A in prevention of corneal graft rejection in rabbits, Br. J. Ophthal.66, 303–308 (1982).Google Scholar
  9. [9]
    R. Berger, J.G. Meingassner andW. Knapp,In vitro effects of cyclosporin A on human B-cell responses, Scand. J. Immunol.17, 241–249 (1983).Google Scholar
  10. [10]
    G.A. Bird, S.M. McLachlan andS. Britton,Cyclosporin A promotes spontaneous outgrowth in vitro of Epstein-Barr virus induced B-cell lines, Nature289, 300–301 (1981).Google Scholar
  11. [11]
    J.T. Blair, A.W. Thomson, P.H. Whiting, R.J.L. Davidson andJ.G. Simpson,Toxicity of the immune suppressant cyclosporin A in the rat, J. Path.138, 163–178 (1982).Google Scholar
  12. [12]
    C. Bolton, G. Allsopp andM.L. Cuzner,The effect of cyclosporin A on the adoptive transfer of experimental allergic encephalomyelitis in the Lewis rat, Clin. exp. Immunol.47, 127–132 (1982).Google Scholar
  13. [13]
    C. Bolton, J.F. Borel, M.L. Cuzner, A.N. Davison andA.M. Turner, Autoimmunity: Cyclosporin A therapy in experimental allergic encephalomyelitis. InCyclosporin A, pp. 135–142. (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  14. [14]
    C. Bolton andM.L. Cuzner, Modification of EAE by nonsteroidal anti-inflammatory drugs. InThe Suppression of Experimental Allergic Ecephalomyelitis and Multiple Sclerosis, p. 189. (EdsA.N. Davison andM.L. Cuzner). Academic Press, London 1980.Google Scholar
  15. [15]
    J. Bordes-Aznar, P.A. Lear, T.B. Strom, N.L. Tilney andJ.W. Kupiec-Weglinski,Kinetics of cyclosporin A-induced unresponsiveness to cardiac allografts in rats, Transplant. Proc.15, 500–503 (1983).Google Scholar
  16. [16]
    J.F. Borel,Cyclosporin A, Triangle20, 97–105 (1981).Google Scholar
  17. [17]
    J.F. Borel, C. Feurer, H.U. Gubler andH. Stähelin,Biological effects of cyclosporin A: a new antilymphocytic agent, Agents and Actions6, 468–475 (1976).Google Scholar
  18. [18]
    J.F. Borel, C. Feurer, C. Magnée andH. Stähelin,Effects of the new anti-lymphocytic peptide cyclosporin A in animals, Immunology32, 1017–1025 (1977).Google Scholar
  19. [19]
    J.F. Borel andJ. Meszaros,Skin transplantation in mice and dogs-effect of cyclosporin A and dihydrocyclosporin C, Transplantation29, 161–162 (1980).Google Scholar
  20. [20]
    J.F. Borel andD. Wiesinger, Effect of cyclosporin A on murine lymphoid cells. InRegulatory Mechanisms in Lymphocyte Activation. Proceedings of the 11th Leukocyte Culture Conference, p. 716 (Ed.D. O. Lucas). Academic Press, New York 1977.Google Scholar
  21. [21]
    J.C.C. Borleffs, Z. de By-Aghai andR.L. Marquet,Beneficial influence of cyclosporin A and standard immunosuppression on kidney graft survival in transfused rhesus monkeys, Transplantation32, 161–162 (1981).Google Scholar
  22. [22]
    J.C.C. Borleffs, P. Neuhaus, R.L. Marquet, C. Zurcher andH. Balner, Cyclosporin A and kidney transplantation in rhesus monkeys. InCyclosporin A, pp. 329–342. (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  23. [23]
    S. Britton andR. Palacios,Cyclosporin A — usefulness, risks and mechanism of action, Immunol. Rev.65, 5–22 (1982).Google Scholar
  24. [24]
    D. Bunjes, C. Hardt, M. Röllinghoff andH. Wagner,Cyclosporin A Mediates Immunosuppression of Primary Cytotoxic T Cell Responses by Impairing the Release of Interleukin 1 and Interleukin 2, Eur. J. Immunol.11, 657–661 (1981).Google Scholar
  25. [25]
    J. Burckhardt andB. Guggenheim,Cyclosporin A: in vivo and in vitro suppression of rat T-lymphocyte function, Immunology36, 753–757 (1979).Google Scholar
  26. [26]
    R.Y. Calne, K. Rolles, D.J.G. White, S. Thiru, D.B. Evans, P. McMaster, D.C. Dunn, G.N. Craddock, R.G. Henderson, S. Aziz andP. Lewis,Cyclosporin A initially as the only immuno-suppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases and 2 livers, Lancet2, 1033–1036 (1979).Google Scholar
  27. [27]
    R.Y. Calne andD.J.G. White,Cyclosporin A — a powerful immunosuppressant in dogs with renal allografts, IRCS Med. Sci.5, 595 (1977).Google Scholar
  28. [28]
    R.Y. Calne, D.J.G. White, D.B. Evans, S. Thiru, R.G. Henderson, D.V. Hamilton, K. Rolles, P. McMaster, T.J. Duffy, B.R.D. MacDougall andR. Williams,Cyclosporin A in cadaveric organ transplantation, Br. med. J.282, 934–936 (1981).Google Scholar
  29. [29]
    R.Y. Calne, D.J.G. White, B.D. Pentlow, K. Rolles, T. Syrakos, T. Ohtawa, D.P. Smith, P. McMaster, D.B. Evans, B.M. Herbertson, andS. Thiru,Cyclosporin A: preliminary observations in dogs with pancreatic duodenal allografts and patients with cadaveric renal transplants, Transplant. Proc.11, 860–864 (1979).Google Scholar
  30. [30]
    R.Y. Calne, D.J.G. White, K. Rolles, D.P. Smith andB.M. Herbertson,Prolonged survival of pig orthotopic heart grafts treated with cyclosporin A, Lancet 1, 1183–1185 (1978).Google Scholar
  31. [31]
    S. Cammisuli, The effect of cyclosporin A on cell interactions within the immune system. In:Cyclosporin A, pp. 243–259. (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  32. [32]
    K.O. Cox, A.C. Allison andB. Samcewicz,Experimental erythrocyte autoimmunity prevented by suppressor T cells in mice treated with cyclosporin A, Clin. Immunol. Immunopathol.28, 90–95 (1983).Google Scholar
  33. [33]
    C. Cunningham, P.H. Whiting, M.D. Burke, D.N. Wheatley andJ.G. Simpson,Increasing the hepatic metabolism of cyclosporine abolishes nephrotoxicity, Transplant. Proc.15, Suppl. 1, 2712–2715 (1983).Google Scholar
  34. [34]
    H.J. Deeg, R.C. Hackman, P.L. Weiden andR. Storb,Growth of canine tumors transplanted into normal adult dogs immunosuppressed by cyclosporin A, Cancer Immunol. & Immunother.12, 147–152 (1982).Google Scholar
  35. [35]
    H.J. Deeg, R. Storb, L. Gerhard-Miller, H.M. Shulman, P.L. Weiden andE.D. Thomas,Cyclosporin A, a powerful immunosuppressant in vivo and in vitro in the dog, fails to induce tolerance, Transplantation29, 230–235 (1980).Google Scholar
  36. [36]
    H.J. Deeg, R. Storb, P.L. Weiden, T. Graham, K. Atkinson andE.D. Thomas,Cyclosporin A: effect on marrow engraftment and graft-versus-host disease in dogs, Transplant. Proc.13, 402–405 (1981).Google Scholar
  37. [37]
    S. Denham, J.M. Styles, R.K. Barfoot andC.J. Dean,Reversible suppression of allo-antibody production by cyclosporin A, Int. Archs Allergy appl. Immun.62, 453–458 (1980).Google Scholar
  38. [38]
    H. Dieperink, H. Starklint andP.C. Leyssac,Nephrotoxicity of cyclosporine — an animal model, Transplant. Proc.15, Suppl. 1, 2736–2741 (1983).Google Scholar
  39. [39]
    D.W. Dongworth andG.G.B. Klaus,Effects of cyclosporin A on the immune system of the mouse, Eur. J. Immunol.12, 1018–1022 (1982).Google Scholar
  40. [40]
    D.C. Dunn, D.J.G. White, B.M. Herbertson andJ. Wade,Prolongation of kidney survival during and after cyclosporin A therapy, Transplantation27, 359–361 (1979).Google Scholar
  41. [41]
    D.F. Du Toit, H. Reece-Smith, P. McShane, T. Denton andP.J. Morris,Effect of cyclosporin A on allotransplanted pancreatic fragments to the spleen of totally pancreatectomized dogs, Transplantation33, 302–307 (1982).Google Scholar
  42. [42]
    S.A. Eccles, S.E. Heckford andP. Alexander,Effect of cyclosporin A on the growth and spontaneous metastasis of syngeneic animal tumours, Br. J. Cancer42, 252–259 (1980).Google Scholar
  43. [43]
    M.J.G. Farthing, M.L. Clark, A. Pendry, J. Sloane andP. Alexander,Nature of the toxicity of cyclosporin A in the rat, Biochem. Pharmac.30, 3311–3316 (1981).Google Scholar
  44. [44]
    R.M. Ferguson, D.E.R. Sutherland, R.L. Simmons andJ.S. Najarian,Ketoconazole, cyclosporin metabolism and renal transplantation, Lancet 2, 882–883 (1982).Google Scholar
  45. [45]
    R.K. Fidelus, R.M. Ferguson, M.B. Widmer, S.-L. Wee, F.H. Bach andC.G. Orosz,Effect of cyclosporin A on murine and human T helper cell clones, Transplantation34, 308–311 (1982).Google Scholar
  46. [46]
    R. Foa andD. Catovsky,Inhibitory effect of cyclosporin A on peripheral blood and bone marrow T lymphocyte colony formation, Clin. exp. Immunol.45, 371–375 (1981).Google Scholar
  47. [47]
    J.F.W. Garvey, P. McShane, M.D. Poole, P.R. Millard andP.J. Morris,The effect of cyclosporin A on experimental pancreas allografts in the rat, Transplant. Proc.12, 266–269 (1980).Google Scholar
  48. [48]
    M.Y. Gordon andJ.W. Singer,Selective effects of cyclosporin A on colony-forming lymphoid and myeloid cells in man, Nature, Lond.279, 433–434 (1979).Google Scholar
  49. [49]
    A. Gratwohl, K. Forster andB. Speck,Skin grafts in rabbits with cyclosporin A; absence of induction of tolerance and untoward side effects, Transplantation31, 136–138 (1981).Google Scholar
  50. [50]
    A. Gratwohl, I. Forster andB. Speck,Histioincompatible skin and marrow grafts in rabbits on cyclosporin A, Transplantation33, 361–364 (1982).Google Scholar
  51. [51]
    A. Gratwohl, B. Speck, M. Wenk, I. Forster, M. Müller, B. Osterwalder, C. Nissen, andF. Follath,Cyclosporin in human bone marrow transplantation; serum concentration, graft-versus-host disease and nephrotoxicity, Transplantation36, 40–44 (1983).Google Scholar
  52. [52]
    C.J. Green andA.C. Allison,Extensive prolongation of rabbit kidney allograft survival after short-term cyclosporin A treatment, Lancet1, 1182–1183 (1978).Google Scholar
  53. [53]
    C.J. Green, A.C. Allison andS. Precious,Induction of specific tolerance in rabbits by kidney allografting and short periods of cyclosporin A treatment, Lancet2, 123–125 (1979).Google Scholar
  54. [54]
    C.J. Green, G. Grimaldi, S. Simpkin andA. Johnson, Immunosuppression of rabbit ovarian and adnexal allografts with cyclosporin A. InCyclosporin A, pp. 165–171. (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam Press, Amsterdam, 1982.Google Scholar
  55. [55]
    C.J. Green, E. Kemp, G. Kemp, S. Larsen, H. Starklint andS. Simpkin, Prolongation of concordant renal xenografts in rabbit recipients by a short course of cyclosporin A treatment. InCyclosporin A, pp. 155–163. (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  56. [56]
    B.M. Hall, M.E. Jelbart andS.E. Dorsch,Alloreactivity in rats treated with cyclosporin A to prolong cardiac graft survival, Transplant. Proc.15, 504–507 (1983).Google Scholar
  57. [57]
    D.V. Hamilton, D.B. Evans andS. Thiru, Toxicity of cyclosporin in organ grafting. InCyclosporin A, pp. 393–411. (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  58. [58]
    P. Häyry, J. Ahonen, E. von Willebrand, B. Eklund, K. Höckekstedt, A. Kauste, E. Taskinen, I. Lautenschlager, M. Lalla andH. Sarelin,Effect of cyclosporin A on the in situ inflammatory response of human renal allograft rejection. A preliminary report, Scand. J. Immunol.16, 135–149 (1982).Google Scholar
  59. [59]
    P. Häyry andT. Paavonen,Effect of cyclosporin A on T-dependent and T-independent immunoglobulin synthesis in vitro, Nature, Lond.287, 542–544 (1980).Google Scholar
  60. [60]
    B. Hermann andW. Mueller,Die Therapie der Chronischen Polyarthritis mit Cyclosporin A, Einen Neuen Immunosuppressivum, Akt. Rheumatol.,4, 173–183 (1979).Google Scholar
  61. [61]
    A.D. Hess, A.D. Donnenberg, P.J. Tutschka andG.W. Santos,Effect of cyclosporin A on human lymphocyte responses in vitro. V. Analysis of responding T lymphocyte subpopulations in primary MLR with monoclonal antibodies, J. Immun.130, 717–721 (1983).Google Scholar
  62. [62]
    A.D. Hess andP.J. Tutschka, itEffect of cyclosporin A on human lymphocyte responses in vitro. I. CsA allows for the expression of alloantigen-activated suppressor cells while preferentially inhibiting the induction of cytolytic effector lymphocytes in MLR. J. Immun.124, 2601–2608.Google Scholar
  63. [63]
    A.D. Hess, P.J. Tutschka, Z. Pu andG.W. Santos,Effect of cyclosporin A on human lymphocyte responses in vitro. IV. Production of T cell stimulatory growth factors and development of responsiveness to these growth factors in CsA-treated primary MLR cultures, J. Immun.128, 360–367 (1982).Google Scholar
  64. [64]
    A.D. Hess, P.J. Tutschka andG.W. Santos,Effect of cyclosporin A on human lymphocytes in vitro. II. Induction of specific alloantigen unresponsiveness mediated by a nylon wool adherent suppressor cell, J. Immun.126, 961–968 (1981).Google Scholar
  65. [65]
    A.D. Hess, P.J. Tutschka andG.W. Santos,Effect of cyclosporin A on human lymphocyte responses in vitro. III. CsA 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. Immun.128, 355–359 (1982).Google Scholar
  66. [66]
    C.W. Hewitt, K.S. Black, L.A. Fraser, J.G. Osborne, T.J. Sayles, B.M. Achauer, D.C. Martin andD.W. Furnas,Cyclosporin A (CyA) is superior to prior donor-specific blood (DSB) transfusion for the extensive prolongation of rat limb allograft survival, Transplant. Proc.15, 514–517 (1983).Google Scholar
  67. [67]
    W.P. Homan, J.W. Fabre, M.E. French, P.R. Millard, T.G. Denton andP.J. Morris,Reversal of acute rejection episodes by cyclosporin A in dogs receiving renal allografts, Transplantation29, 262–263 (1980).Google Scholar
  68. [68]
    W.P. Homan, J.W. Fabre, P.R. Millard andP.J. Morris,Effect of cyclosporin A upon second-set rejection of rat renal allografts, Transplantation30, 354–357 (1980).Google Scholar
  69. [69]
    W.P. Homan, J.W. Fabre andP.J. Morris,Nature of the unresponsiveness induced by cyclosporin A in rats bearing renal allografts, Transplantation28, 439–441 (1979).Google Scholar
  70. [70]
    W.P. Homan, J.W. Fabre, K.A. Williams, P.R. Millard andP.J. Morris,Studies on the immunosuppressive properties of cyclosporin A in rats receiving renal allografts, Transplantation29, 361–366 (1980).Google Scholar
  71. [71]
    W.P. Homan, K.A. Williams, J.W. Fabre, P.R. Millard andP.J. Morris,Prolongation of cardiac zenograft survival in rats receiving cyclosporin A, Transplantation31, 164–166 (1980).Google Scholar
  72. [72]
    W.P. Homan, K.A. Williams, P.R. Millard andP.J. Morris,Prolongation of renal allograft survival in the rat by pretreatment with donor antigen and cyclosporin A, Transplantation31, 423–427 (1981).Google Scholar
  73. [73]
    T. Horsburgh, P. Wood andL. Brent,Suppression of in vitro lymphocyte reactivity by cyclosporin A: existence of a population of drug-resistant cytotoxic lymphocytes, Nature286, 609–611 (1980).Google Scholar
  74. [74]
    J. Hows, R. Harris, S. Palmer andE.C. Gordon-Smith,Immunosuppression with cyclosporin A in allogeneic bone marrow transplantation for severe aplastic anaemia: preliminary studies, Br. J. Haemat.48, 227–236 (1981).Google Scholar
  75. [75]
    W.T. Hughes andB. Smith,Provocation of infection due to Pneumocystis-carinii by cyclosporin A, J. Infect. Dis.145, 767 (1982).Google Scholar
  76. [76]
    P.A. Hunter, A. Garner, K.R. Wilhelmus, N.S.C. Rice andB.R. Jones,Corneal graft rejection—a new rabbit model and cyclosporin A, Br. J. Ophthal.66, 292–302 (1982).Google Scholar
  77. [77]
    I.F. Hutchinson, C.A. Shadur, J.S.A. Duarte, T.B. Strom andN.L. Tilney,Cyclosporin A spares selectively lymphocytes with donor-specific suppressor characteristics, Transplantation32, 210–216 (1981).Google Scholar
  78. [78]
    M. Introna, P. Allavena, F. Spreafico andA. Mantovani,Inhibition of human natural killer activity by cyclosporin A, Transplantation31, 113–116 (1981).Google Scholar
  79. [79]
    D.A. Isenberg, M.L. Snaith, W.J.W. Morrow, A.A. Al-Khader, S.L. Cohen, C. Fisher andJ. Mowbray,Cyclosporin A for the treatment of systemic lupus erythematosus, Int. J. Immunopharmacol.3, 163–169 (1981).Google Scholar
  80. [80]
    S.W. Jamieson, N.A. Burton, C.P. Bieber, B.A., Reitz, P.E. Oyer, E.E. Stinson andN.E. Shumway,Cardiac allograft survival in primates treated with cyclosporin A, Lancet1, 545 (1979).Google Scholar
  81. [81]
    R.L. Janco andD. English,Cyclosporine and human neutrophil function, Transplantation35, 501–503 (1983).Google Scholar
  82. [82]
    B.D. Kahan, C.T. Van Buren, S.N. Lin, Y. Ono, G. Agostino, S.J. Legrue, M. Boileau W.D. Payne andR.H. Kerman,Immunopharmacological monitoring of cyclosporin A-treated recipients of cadaveric kidney allografts, Transplantation34, 36–45 (1982).Google Scholar
  83. [83]
    V.V. Kalman andG.R. Klimpel,Cyclosporin A inhibits the production of gamma interferon (IFN γ) but does not inhibit production of virus-induced IFN α/β, Cell. Immunol.78, 122–129 (1983).Google Scholar
  84. [84]
    K. Kawahara, D.E.R. Sutherland, J. Rynasiewicz andJ.S. Najarian,Prolongation of heterotopic cardiac allografts in rats by cyclosporin A, Surgery88, 594–600 (1980).Google Scholar
  85. [85]
    J.E. Kay andC.R. Benzie,Effects of cyclosporin A on the metabolism of unstimulated and mitogen-activated lymphocytes, Immunology49, 153–160 (1983).Google Scholar
  86. [86]
    P.A. Keown, C.R. Stiller, R.A. Ulan, N.R. Sinclair, W.J. Wall, G. Carruthers andW. Howson,Immunological and pharmacological monitoring in the clinical use of cyclosporin A, Lancet1, 686–689 (1981).Google Scholar
  87. [87]
    G.G.B. Klaus andA. Kunkl,Effects of cyclosporine in the immune system of the mouse. II. Cyclosporine inhibits the effector function of primary T helper cells, but not helper cell priming, Transplantation36, 80–84 (1983).Google Scholar
  88. [88]
    M. Koponen, A. Grieder andF. Loor,The effects of cyclosporins on the cell cycle of T-lymphoid cell lines, Expl Cell Res.140, 237–250 (1982).Google Scholar
  89. [89]
    A.J. Kostakis, D.J.G. White andR.Y. Calne,Prolongation of rat heart allograft survival by cyclosporin A, IRCS Med. Sci.5, 280 (1977).Google Scholar
  90. [90]
    W. Kreis andA. Soricelli,Cyclosporins: immunosuppressive agents with antitumor activity, Experientia35, 1506–1508 (1979).Google Scholar
  91. [91]
    A. Kunkl andG.G.B. Klaus,Selective effects of cyclosporin A on functional B cell subsets in the mouse, J. Immun.125, 2526–2531 (1980).Google Scholar
  92. [92]
    J.W. Kupiec-Weglinski, P.A. Lear, J. Bordes-Aznar, N.L. Tilney andT.B. Strom,Acute rejection in cyclosporin A-treated graft recipients occurs following abrogation of suppressor cells, Transplant. Proc.15, 531–534 (1983).Google Scholar
  93. [93]
    J.B. Kurtz andW.P. Homan,Murine cytomegalovirus infection and cyclosporin A, Transplantation34, 215–216 (1982).Google Scholar
  94. [94]
    U. Landegren, V. Ramstedt, I. Axberg, A. Örn andH. Wigzell,Cyclosporin A permits the distinction between specific T and NK activity generated in a human MLC, Int. J. Cancer28, 725–730 (1981).Google Scholar
  95. [95]
    E.-L. Larrson,Cyclosporin A and dexamethasone suppress T cell responses by selectively acting at distinct sites of the triggering process, J. Immun.124, 2828–2833 (1980).Google Scholar
  96. [96]
    A. Laupacis, C.R. Stiller, C. Gardell, P. Keown, J. Dupre, A.C. Wallace andP. Thibert,Cyclosporin prevents diabetes in BB Wistar rats, Lancet1, 10–12 (1983).Google Scholar
  97. [97]
    S.B. Leapman, R.S. Filo, E.J. Smith andP.G. Smith,Differential effects of cyclosporin A on lymphocyte sub-populations, Transplant. Proc.13, 405 (1981).Google Scholar
  98. [98]
    S.P.M. Lems, P.J.A. Capel andR.A.P. Koene,Prolongation of mouse skin allograft survival by cyclosporin A. Graft rejection after withdrawal of therapy, Transplant. Proc.12, 283–286 (1980).Google Scholar
  99. [99]
    P. Leoni, R.C. Garcia andA.C. Allison,Effects of cyclosporin A on human lymphocytes in culture, J. Clin. Lab. Immunol.1, 67–72 (1978).Google Scholar
  100. [100]
    A.A. Like, M. Anthony, D.L. Guberski andA.A. Rossini,Spontaneous diabetes mellitus in the BB/W rat. Effects of glucocorticoids, cyclosporin A and antiserum to rat lymphocytes, Diabetes32, 326–330 (1983).Google Scholar
  101. [101]
    N.J. Lindsay, K.R. Harris, H.B. Norman, J.L. Smith, H.A. Lee andM. Slapek,The effect of cyclosporin A on the primary and secondary immune responses in the rabbit, Transplant. Proc.12, 252–255 (1980).Google Scholar
  102. [102]
    K.G. Lurie, M.E. Billingham, S.W. Jamieson, D.C. Harrison andB.A. Reitz,Pathogenesis and prevention of graft arteriosclerosis in an experimental heart transplant model, Transplantation31, 41–47 (1981).Google Scholar
  103. [103]
    J.R. Markwick, J.D. Chambers, J.R. Hobbs andG.D. Pegrum,Timing of cyclosporin A therapy for absorption of HVG and GVH responses in rats, Lancet2, 1037 (1979).Google Scholar
  104. [104]
    B.E. Matter, P. Donatsch, R.R. Racine, B. Schmid andW. Suter,Genotoxicity evaluation of cyclosporin A, a new immuno-suppressive agent, Mutation Research105, 257–264 (1982).Google Scholar
  105. [105]
    G. Maurer, B. Keller andH.R. Loosli,3H-OL 27-400: Isolation and Structure Elucidation of its Metabolites, Document, Sandoz Ltd., Basle (1981).Google Scholar
  106. [106]
    A.M. McGregor, D.P. Rennie, A.P. Weetman, R.A. Hassman, S.M. Foord, C. Dieguez andR. Hall,The influence of cyclosporin A on experimental autoimmune disease in the rat, Life Sci.32, 97–108 (1983).Google Scholar
  107. [107]
    L.C. McIntosh andA.W. Thomson,Activity of the mononuclear phagocyte system in cyclosporin A treated mice, Transplantation30, 384–386 (1980).Google Scholar
  108. [108]
    F.N. McKenzie, C.R. Stiller, W.J. Wall, P. Keown, M.D. Silver, A. Painvin andR.O. Heimbecker,Studies of canine heterotopic heart allografts treated with cyclosporin A, Transplant. Proc.15, 1244–1246 (1983).Google Scholar
  109. [109]
    M.J. Mihatsch, W. Olivieri, I. Marret, G. Thiel, F. Harder andH.U. Zollinger,Giant mitochondria in renal tubular cells and cyclosporin A, Lancet1, 1162–1163 (1981).Google Scholar
  110. [110]
    P.J. Morris,Cyclosporin A, Transplantation32, 349–354 (1981).Google Scholar
  111. [111]
    P.J. Morris, D.R. Finch, J.F. Garvey, M.D. Poole andP.R. Millard,Suppression of rejection of allogeneic islet tissue in the rat, Diabetes29, 107 (1981).Google Scholar
  112. [112]
    A. Muraguchi, J.L. Butler, J.H. Kehrl, R.J.M. Falkoff andA.C. Fauci,Selective suppression of an early step in human B cell activation by cyclosporin A, J. exp. Med.158, 690–702 (1983).Google Scholar
  113. [113]
    T. Nagao, D.J.G. White andR.Y. Calne,Kinetics of unresponsiveness induced by a short course of cyclosporin A, Transplantation33, 31–35 (1982).Google Scholar
  114. [114]
    A. Nemlander, A. Soots, E. Von Willebrand, G. Tallqvist andP. Häyry,Effect of cyclosporin A on the in situ inflammatory response of rat renal allograft rejection, Scand. J. Immunol.16, 91–102 (1982).Google Scholar
  115. [115]
    W. Niederberger, M. Lemaire, K. Nussbaumer, G. Maurer andO. Wagner,Distribution of cyclosporine in blood components and tissues, Transplant. Proc. Suppl. In Press (1983).Google Scholar
  116. [116]
    A.J. Norin, E.E. Emeson andF.J. Veith,Unresponsiveness to lung allografts in mongrel dogs after cessation of cyclosporin A therapy, Transplant. Proc.15, 508–510 (1983).Google Scholar
  117. [117]
    A.J. Norin, F.J. Veith, E.E. Emeson, C.M. Montefusco, K.L. Pinsker andS.L. Kamholz,Improved survival of transplanted lungs in mongrel dogs treated with cyclosporin A, Transplantation32, 259–260 (1981).Google Scholar
  118. [118]
    J.S. Nowak, O. Kai, R. Peck andR.M. Franklin,The effects of cyclosporin A on the chicken immune system, Eur. J. Immunol.12, 867–876 (1982).Google Scholar
  119. [119]
    R.B. Nussenblatt, A.G. Palestine, A.H. Rook, I. Scher, W.B. Wacker andI. Gery,Treatment of intraocular inflammatory disease with cyclosporin A, Lancet2, 235–238 (1983).Google Scholar
  120. [120]
    R.B. Nussenblatt, M.M. Rodrigues, M.C. Salinas-Carmona, I. Gery, S. Cevario andW. Wacker,Modulation of experimental autoimmune uveitis with cyclosporin A, Archs. Ophthal.100, 1146–1149 (1982).Google Scholar
  121. [121]
    R.B. Nussenblatt, M.M. Rodrigues, W.B. Wacker, S.J. Cevario, M.C. Salinas-Carmona andI. Gery,Cyclosporin A. Inhibition of experimental autoimmune uveitis in Lewis rats, J. clin. Invest.67, 1228–1231 (1981).Google Scholar
  122. [122]
    C.G. Orosz, R.K. Fidelus, D.C. Roopenian, M.B. Widmer, R.M. Ferguson andF.H. Bach,Analysis of cloned T cell function. I. Discussion of cloned T cell proliferative responses using cyclosporin A, J. Immun.129, 1865–1868. (1982).Google Scholar
  123. [123]
    T. Paavonen, H. Järveläinen, S. Kontiainen andP. Häyry,Effect of cyclosporin A on in vitro proliferative activity and immunoglobulin synthesis of isolated human lymphoid cell subpopulations, Clin. exp. Immunol.43, 342–350 (1981).Google Scholar
  124. [124]
    R. Palacios,Cyclosporin A inhibits the proliferative response and the generation of helper, suppressor and cytotoxic T-cell functions in the autologous mixed lymphocyte reaction, Cell. Immunol.61, 453–462 (1981).Google Scholar
  125. [125]
    R. Palacios,Cyclosporin A abrogates proliferation of T cells and generation of suppressor and cytotoxic T-cell function induced by Epstein-Barr virus, Immunobiology160, 321–329 (1981).Google Scholar
  126. [126]
    R. Palacios,Concanavalin A triggers T lymphocytes by directly interacting with their receptors for activation, J. Immun.128, 337–342 (1982).Google Scholar
  127. [127]
    R. Palacios andG. Möller,Cyclosporin A blocks receptors for HLA-DR antigens on T cells, Nature290, 792–794 (1981).Google Scholar
  128. [128]
    D. Parker, K. Drössler andJ.L. Turk,Kinetics of the effect of a single dose of cyclosporin A on antibody and cell-mediated immune responses in the guinea pig, Int. J. Immunopharmac6, 67–74 (1984).Google Scholar
  129. [129]
    A. Pendry andP. Alexander, Stimulation of hair growth on nude mice by cyclosporin A. InCyclosporin A pp. 77–81. (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  130. [130]
    J.L. Pennock, B.A. Reitz, C.P. Bieber, A. Aziz, P.E. Oyer, S. Strober, R. Hoppe, H.S. Kaplan, E.B. Stinson andN.E. Shumway,Survival of primates following orthotopic cardiac transplantation treated with total lymphoid irradiation and chemical immune suppression, Transplantation32, 467–473 (1981).Google Scholar
  131. [131]
    J.L. Pennock, B.A. Reitz, C.P. Bieber, S.W. Jamieson, N.A. Burton, A.A. Raney, P.E. Oyer andE.B. Stinson,Lethal complications due to cyclosporin A immune suppression with combination drug and combined heart and lung transplantation, Surg. Forum31, 375–378 (1980).Google Scholar
  132. [132]
    T.J. Petcher, H.P. Weber andA. Rüegger,Crystal and molecular structure of an iodo-derivative of the cyclic undecapeptide cyclosporin A, Helv. chim. Acta59, 1480–1488 (1976).Google Scholar
  133. [133]
    R.L. Powles, H.M. Clink, D. Spence, G. Morgenstern, J.G. Watson, P.J. Selby, M. Woods, A. Barrett, B. Jameson, J. Sloane, S.D. Lawler, H.E.M. Kay, D. Lawson, T.J. McElwain andP. Alexander,Cyclosporin A to prevent graft-versus-host disease in man after allogeneic bone marrow transplantation, Lancet1, 327–329 (1980).Google Scholar
  134. [134]
    Preliminary Results of a European Multicentre Trial,Cyclosporin A as sole immunosuppressive agent in recipients of kidney allografts from cadaver donors, Lancetii, 57–60 (1982).Google Scholar
  135. [135]
    A. Procyshyn, P. McMaster, R.Y. Calne, R. Valdes andK. Rolles,Successful prolongation of canine pancreas allografts with cyclosporin A, Br. J. Surg.66, 907 (1979).Google Scholar
  136. [136]
    J. Prop, H.L. Bartels, A.H. Petersen, C.R.H. Wildevuur andP. Nieuwenhuis,A single injection of cyclopsorin A reverses lung allograft rejection in the rat, Transplant. Proc.15, 511–513 (1983).Google Scholar
  137. [137]
    H. Reece-Smith, D.F. Du Toit, P. McShane andP.J. Morris,Effect of cyclosporin A on rejection of pancreatic islets transplanted under the renal capsule, Transplantation32, 333–334 (1981).Google Scholar
  138. [138]
    H. Reece-Smith, W.P. Homan, D.F. Du Toit, P. McShane andP.J. Morris A technique for transplanting pancreatic islets as a vascularized graft and prevention of rejection with cyclosporin A, Transplantation31, 442–444 (1981).Google Scholar
  139. [139]
    B.A. Reitz, C.P. Bieber andJ.L. Pennock, Cyclosporin A and lymphoma in non-human primates. InCyclosporin A, pp. 317–328. (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  140. [140]
    G. Routheier, O. Epstein, G. Janossy, H.C. Thomas, S. Sherlock, P.C. Kung andG. Goldstein,Effects of cyclosporin A on suppressor and inducer T lymphocytes in primary biliary cirrhosis, Lancet2, 1223–1226 (1980).Google Scholar
  141. [141]
    B. Ryffel, Experimental toxicological studies with cyclosporin A. InCyclosporin A, pp. 45–75. (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  142. [142]
    B. Ryffel, H. Deyssenroth andJ.F. Borel, Cyclosporin A: effects on the mouse thymus, Agents and Actions11, 373–379 (1981).Google Scholar
  143. [143]
    B. Ryffel, P. Donatsch, M. Madörin, B.E. Matter, G. Rüttimann, H. Schön, R. Stoll andJ. Wilson,Toxicological evaluation of cyclosporin A, Arch. Toxicol.53, 107–141 (1983).Google Scholar
  144. [144]
    J.J. Rynasiewicz, D.E.R. Sutherland, K. Kawahara, P. Gorecki andJ.S. Najarian,Cyclosporin A prolongation of segmental pancreatic and islet allograft function in rats, Transplant. Proc.12, 270–274 (1980).Google Scholar
  145. [145]
    C. Shao-Hsien, I. Lang, H. Gunn andP. Lydyard,Effect of in vitro cyclosporin A treatment on human natural and antibody-dependent cell-mediated cytotoxicity, Transplantation35, 127–129 (1983).Google Scholar
  146. [146]
    W.F.I. Shepherd, D.J. Coster, T. Chin Fook, N.S.C. Rice andB.R. Jones,Effect of cyclosporin A on the survival of corneal grafts in rabbits, Br. J. Ophthal.64, 148–153 (1980).Google Scholar
  147. [147]
    H. Siegl, R. Petric andB. Ryffel,Effects of cyclosporine on renin-angiotensin-aldosterone, Transplant. Proc.15, Suppl. 1, 2719–2725 (1983).Google Scholar
  148. [148]
    H. Siegl andB. Ryffel,Effect of cyclosporin on renin-angiotensin-aldosterone system, Lancet2, 1274 (1982).Google Scholar
  149. [149]
    M.H. Simms, J.K. Cruickshank, J.D. Blainey, A.H. Cameron andA.D. Barnes,Effects of cyclosporin A in rat kidney grafts, Transplant. Proc.12, 256–260 (1980).Google Scholar
  150. [150]
    J.G. Simpson, J.T. Blair, P.H. Whiting andA.W. Thomson,Cyclosporin A-induced renal proximal tubular damage, IRCS Med. Sci.9, 562–563 (1981).Google Scholar
  151. [151]
    G.N. Smith,The effect of cyclosporin A on the primary immune response to allogeneic red cells in rabbits, Immunology45, 163–167 (1982).Google Scholar
  152. [152]
    T.E. Starzl, R. Weil, S. Iwatsuki, G. Klintmalm, G.P.J. Schrõter, L.J. Koep, Y. Iwaki, P.E. Terasaki andK.A. Porter,The use of cyclosporin A and prednisone in cadaver kidney transplantation, Surgery Gynec. Obstet.151, 17–26 (1980).Google Scholar
  153. [153]
    P. Sweny andN. Tidman,The effect of cyclosporin A on peripheral blood T cell subpopulations in renal allografts, Clin. exp. Immunol.47, 445–448 (1982).Google Scholar
  154. [154]
    A.W. Thomson, D.K. Moon, C.L. Geczy andD.S. Nelson,Cyclosporin A and lymphokines affecting macrophage behaviour, Transplant. Proc.15, Suppl. 1, 2390–2393 (1983).Google Scholar
  155. [155]
    A.W. Thomson, D.K. Moon, C.L. Geczy andD.S. Nelson,Cyclosporin A inhibits lymphokine production but not the responses of macrophages to lymphokines, Immunology48, 291–299 (1983).Google Scholar
  156. [156]
    A.W. Thomson, D.K. Moon, Y. Inoue, C.L. Geczy andD.S. Nelson,Modification of delayed-type hypersensitivity reactions to ovalbumin in cyclosporin A-treated guinea pigs, Immunology48, 301–308 (1983).Google Scholar
  157. [157]
    A.W. Thomson, D.K. Moon andD.S. Nelson,Inhibition of delayed-type hypersensitivity reactions and lymphokine production by cyclosporin A in the mouse, Clin. exp. Immunol.52, 599–606 (1983).Google Scholar
  158. [158]
    A.W. Thomson, P.H. Whiting, J.T. Blair, R.J.L. Davidson andJ.G. Simpson,Pathological changes developing in the rat during a 3-week course of high dosage cyclosporin A and their reversal following drug withdrawal, Transplantation32, 271–277 (1981).Google Scholar
  159. [159]
    A.W. Thomson, P.H. Whiting, I.D. Cameron, S.E. Lessels andJ.G. Simpson,A toxicological study in rats receiving immunotherapeutic doses of cyclosporin A, Transplantation31, 121–124 (1981).Google Scholar
  160. [160]
    A.W. Thomson, P.H. Whiting andJ.G. Simpson, Pathobiology of cyclosporin A in experimental animals. InCyclosporin A, pp. 177–190. (EdD.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  161. [161]
    C. Tomkins, R.H.M. King andP.K. Thomas,Modification of expeerimental allergic neuritis by cyclosporin A, Neuropathol. Appl. Neurobiol.6, 240 (1980).Google Scholar
  162. [162]
    G. Tosato, S.E. Pike, I.R. Koski andR.M. Blaese,Selective inhibition of immunoregulatory cell functions by cyclosporin A, J. Immun.128, 1986–1991 (1982).Google Scholar
  163. [163]
    P.J. Tutschka, W.E. Beschorner, A.C. Allison, W.H. Burns andG.W. Santos,Use of cyclosporin A in allogeneic bone marrow transplantation (BMT) in the rat, Nature280, 148–151 (1979).Google Scholar
  164. [164]
    D.W. Van Bekkum, S. Knaan andC. Zurcher,Effects of cyclosporin A on experimental graft-versus-host disease (GVHD) in rodents, Transplant. Proc.12, 278–282 (1980).Google Scholar
  165. [165]
    F.J. Veith, A.J. Norin, C.M. Montefusco, K.L. Pinsker, S.L. Kamholz, M.L. Gliedman andE. Emeson,Cyclosporin A in experimental lung transplantation, Transplantation32, 474–481 (1981).Google Scholar
  166. [166]
    B. Vialettes, M.C. Simon, V. Lassmann andP.H. Vague,Prolonged survival of allotransplanted islets of Langerhans after cyclosporin A treatment in rats, Transplantation28, 435–436 (1979).Google Scholar
  167. [167]
    A.O. Vladutiu,Effect of cyclosporine on experimental autoimmune thyroiditis in mice, Transplantation35, 518–520 (1983).Google Scholar
  168. [168]
    E. Von Willerbrand andP. Häyry,Cyclosporin A deposits in renal allografts, Lancet2, 189–192 (1983).Google Scholar
  169. [169]
    H. Wagner,Cyclosporin A: mechanism of action, Transplant. Proc.15, 523–526 (1983).Google Scholar
  170. [170]
    O. Wagner, Absorption and Excretion of3H-OL 27-400 (Drink Solution) in dogs, Document, Sandoz Ltd., Basle (1981).Google Scholar
  171. [171]
    J. Wallwork, C.G.A., McGregor, F.C. Wells, R. Cory-Pearce andT.A.H. English,Cyclosporin and intravenous sulphadimidine and trimethoprim therapy, Lancet1, 366–367 (1983).Google Scholar
  172. [172]
    B.S. Wang, E.H. Heacock, K.H. Collins, I.F. Hutchinson, N.L. Tilney andJ.A. Mannick,Suppressive effects of cyclosporin A on the induction of alloreactivity in vitro and in vivo, J. Immun.127, 89–93 (1981).Google Scholar
  173. [173]
    D.J. Watt, T.A. Partridge andJ.C. Sloper,Cyclosporin A as a means of preventing rejection of skeletal muscle allografts in mice, Transplantation31, 266–271 (1981).Google Scholar
  174. [174]
    R. Wenger, Chemistry of cyclosporin. InCyclosporin A, pp. 19–34. (Ed.D.J.G. White). Elsevier Biomedical Press, Amsterdam 1982.Google Scholar
  175. [175]
    D.J.G. White, A.M. Plumb, G. Pawelec andG. Brons,Cyclosporin A: an immunosuppressive agent preferentially active against proliferating T cells, Transplantation27, 55–58 (1979).Google Scholar
  176. [176]
    D.J.G. White, K. Rolles, T. Ottawa andO. Turell,Cyclosporin A induced long-term survival of fully incompatible skin and heart grafts in rats, Transplant. Proc.12, 261–265 (1980).Google Scholar
  177. [177]
    P.H. Whiting, C. Cunningham, A.W. Thomson andJ.G. Simpson,Enhancement of high dose cyclosporin A toxicity by frusemide, Biochem. Pharmac.33, 1075–1079 (1984).Google Scholar
  178. [178]
    P.H. Whiting andJ.G. Simpson,The enhancement of cyclosporin A-induced nephrotoxicity by gentamicin, Biochem. Pharmac.32, 2025–2028 (1983).Google Scholar
  179. [179]
    P.H. Whiting, J.G. Simpson, R.J.L. Davidson andA.W. Thomson,The toxic effects of combined administration of cyclosporin A and gentamicin, Br. J. exp. Path.63, 554–561 (1982).Google Scholar
  180. [180]
    P.H. Whiting, J.G. Simpson, R.J.L. Davidson andA.W. Thomson,Pathological changes in rats receiving cyclosporin A at immunotherapeutic dosage for 7 weeks, Br. J. exp. Path.64, 437–444 (1983).Google Scholar
  181. [181]
    P.H. Whiting, A.W. Thomson, J.T. Blair andJ.G. Simpson,Experimental cyclosporin A nephrotoxicity, Br. J. exp. Path.63, 88–94 (1982).Google Scholar
  182. [182]
    P.H. Whiting, A.W. Thomson andJ.G. Simpson,Renal and hepatic function in rats treated with gentamicin or cephalosporin antibiotics, Br. J. exp. Path.64, 693–701 (1983).Google Scholar
  183. [183]
    G. Wick, P.-U. Müller andS. Schwarz,Effect of cyclosporin A on spontaneous autoimmune thyroiditis of obese strain (OS) chickens, Eur. J. Immunol.12, 877–881 (1982).Google Scholar
  184. [184]
    R.H. Yanagihara andW.H. Adler,Inhibition of mouse natural killer activity by cyclosporin A, Immunology45, 325–332 (1982).Google Scholar
  185. [185]
    A.A. Zalewski andA.K. Gulati,Survival of nerve and Schwann cells in allografts after cyclosporin A treatment, Expl Neurol.70, 219–225 (1980).Google Scholar
  186. [186]
    F.A. Zimmerman, D.J.G. White, R. Grantzow, H.G. Dietz, S. Dorn-Kling andJ.M. Gokel,Immunosuppressive therapy in liver and small bowel grafts in the rat, Z. Kinderchir.30, 177–180 (1980).Google Scholar
  187. [187]
    A. Zschauer andCh. Hodel,Drug-induced changes in rat seminiferous tubular epithelium, Arch. Toxicol. Suppl.4, 466–470 (1980).Google Scholar

Copyright information

© Birkhäuser Verlag 1984

Authors and Affiliations

  • A. W. Thomson
    • 1
  • P. H. Whiting
    • 1
  • J. G. Simpson
    • 1
  1. 1.Departments of Pathology and Chemical PathologyUniversity Medical BuildingsAberdeenScotland, UK

Personalised recommendations