Skip to main content

Advertisement

SpringerLink
Log in

Systemic cyclosporine and corneal transplantation

  • Review
  • Published:
International Ophthalmology Aims and scope Submit manuscript

Abstract

Corneal transplantation is the most commonly performed tissue transplant boasting over a century of history, science, and tradition. While favorable outcomes have been reported after penetrating keratoplasty, rejection remains a major cause of graft failure. The long-term survival rates of this relatively immunologically privileged tissue are only just comparable to those of vascularized organs. While corticosteroids treatment remains the gold standard for postoperative immunomodulation, other agents have been utilized in an ongoing effort to improve graft survival and patient outcomes. One of the most promising immunomodulatory substances whose immunosuppressive effect has revolutionized solid organ transplantation is cyclosporine (CsA). A calcineurin inhibitor, cyclosporine has been used as an immunosuppressive agent in corneal transplantation since the 1980’s. Although some studies have shown beneficial effects of cyclosporine in both low- and high-risk corneal transplant patients the use of cyclosporine in rejection prophylaxis and treatment remain controversial and disputable. We herein present a literature review on the role of systemic cyclosporine in corneal transplantation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. The collaborative corneal transplantation studies (CCTS) (1992) Effectiveness of histocompatibility matching in high-risk corneal transplantation. The Collaborative Corneal Transplantation Studies Research Group. Arch Ophthalmol 110(10):1392–1403

    Article  Google Scholar 

  2. Bradley BA et al (1993) Penetrating keratoplasty in the United Kingdom: an interim analysis of the corneal transplant follow-up study. Clin Transpl 293–315

  3. Williams KA et al (2006) The Australian corneal graft registry 2004 annual report. http://hdl.handle.net/2328/1002

  4. Hill JC (2002) High risk corneal grafting. Br J Ophthalmol 86(9):945

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Khodadoust AA (1973) The allograft rejection reaction: the leading cause of late failure of clinical corneal grafts. In: Corneal graft failure. Ciba Foundation Symposium 15, new series. Elsevier. pp. 151–67

  6. Report of the organ transplant panel (1988) Corneal transplantation. Council on scientific affairs. JAMA 259(5):719–722

    Article  Google Scholar 

  7. Hoffmann F, Wiederholt M (1985) Local treatment of corneal transplants in the human with cyclosporin A. Klin Monbl Augenheilkd 187(2):92–96

    Article  PubMed  CAS  Google Scholar 

  8. Borel JF et al (1976) Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 6(4):468–475

    Article  PubMed  CAS  Google Scholar 

  9. European Multicentre Trial Group (1983) Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet 2(8357):986–989

    Article  Google Scholar 

  10. Calne RY et al (1979) Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 2(8151):1033–1036

    Article  PubMed  CAS  Google Scholar 

  11. Claerhout I et al (2001) The effect of duration and timing of systemic cyclosporine therapy on corneal allograft survival in a rat model. Graefes Arch Clin Exp Ophthalmol 239(2):152–157

    Article  PubMed  CAS  Google Scholar 

  12. Nussenblatt RB, Palestine AG (1986) Cyclosporine: immunology, pharmacology and therapeutic uses. Surv Ophthalmol 31(3):159–169

    Article  PubMed  CAS  Google Scholar 

  13. Hoffmann F, Wiederholt M (1986) Topical cyclosporin A in the treatment of corneal graft reaction. Cornea 5(3):129

    Article  PubMed  CAS  Google Scholar 

  14. Kahan BD (1989) Cyclosporine. N Engl J Med 321(25):1725–1738

    Article  PubMed  CAS  Google Scholar 

  15. Belin MW, Bouchard CS, Phillips TM (1990) Update on topical cyclosporin A. Background, immunology, and pharmacology. Cornea 9(3):184–195

    Article  PubMed  CAS  Google Scholar 

  16. Petcher TJ, Weber H, Ruegger A (1976) Crystal and molecular structure of an iodo-derivative of the cyclic undecapeptide cyclosporin A. Helv Chim Acta 59(5):1480–1489

    Article  PubMed  CAS  Google Scholar 

  17. Perry HD, Donnenfeld ED (2004) Topical 0.05% cyclosporin in the treatment of dry eye. Expert Opin Pharmacother 5(10):2099–2107

    Article  PubMed  CAS  Google Scholar 

  18. Pleyer U et al (1994) Ocular absorption of cyclosporine A from liposomes incorporated into collagen shields. Curr Eye Res 13(3):177–181

    Article  PubMed  CAS  Google Scholar 

  19. Pleyer U et al (1993) Verteilung von Cyclophilin in okulären Geweben. Ophthalmologe 90:118

    Google Scholar 

  20. Liu J (1993) FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. Immunol Today 14(6):290–295

    Article  PubMed  CAS  Google Scholar 

  21. Fruman DA et al (1992) Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci USA 89(9):3686–3690

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Halloran PF, Kung L, Noujaim J (1998) Calcineurin and the biological effect of cyclosporine and tacrolimus. Transplant Proc 30(5):2167–2170

    Article  PubMed  CAS  Google Scholar 

  23. Horsley V, Pavlath GK (2002) NFAT: ubiquitous regulator of cell differentiation and adaptation. J Cell Biol 156(5):771–774

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Waldmeier PC et al (2003) Cyclophilin D as a drug target. Curr Med Chem 10(16):1485–1506

    Article  PubMed  CAS  Google Scholar 

  25. Foulks GN (2006) Topical cyclosporine for treatment of ocular surface disease. Int Ophthalmol Clin 46(4):105–122

    Article  PubMed  Google Scholar 

  26. Avunduk AM et al (2003) The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye patients: a clinical and immunocytochemical study. Am J Ophthalmol 136(4):593–602

    Article  PubMed  CAS  Google Scholar 

  27. Maguire MG et al (1994) Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies. Collaborative Corneal Transplantation Studies Research Group. Ophthalmology 101(9):1536–1547

    Article  PubMed  CAS  Google Scholar 

  28. Newton C, Gebhardt BM, Kaufman HE (1988) Topically applied cyclosporine in azone prolongs corneal allograft survival. Invest Ophthalmol Vis Sci 29(2):208–215

    PubMed  CAS  Google Scholar 

  29. Yoon KC et al (2008) Effect of topical cyclosporin A on herpetic stromal keratitis in a mouse model. Cornea 27(4):454–460

    Article  PubMed  Google Scholar 

  30. Rao SN (2006) Treatment of herpes simplex virus stromal keratitis unresponsive to topical prednisolone 1% with topical cyclosporine 0.05%. Am J Ophthalmol 141(4):771–772

    Article  PubMed  CAS  Google Scholar 

  31. Tedesco D, Haragsim L (2012) Cyclosporine: a review. J Transplant 2012:230386

    Article  PubMed  PubMed Central  Google Scholar 

  32. Scheer S et al (2003) Immunosuppression in corneal transplantation. J Fr Ophtalmol 26(6):637–647

    PubMed  CAS  Google Scholar 

  33. Bertelmann E, Jaroszewski J, Pleyer U (2002) Corneal allograft rejection: current understanding. 2. Clinical implications. Ophthalmologica 216(1):2–12

    Article  PubMed  Google Scholar 

  34. Wood AJ et al (1983) Cyclosporine: pharmacokinetics, metabolism, and drug interactions. Transplant Proc 15:2409–2414

    CAS  Google Scholar 

  35. Naesens M, Kuypers DR, Sarwal M (2009) Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4(2):481–508

    PubMed  CAS  Google Scholar 

  36. Hesselink DA, Bouamar R, van Gelder T (2010) The pharmacogenetics of calcineurin inhibitor-related nephrotoxicity. Ther Drug Monit 32(4):387–393

    Article  PubMed  CAS  Google Scholar 

  37. de Smet MD, Nussenblatt RB (1993) Clinical use of cyclosporine in ocular disease. Int Ophthalmol Clin 33(4):31–45

    Article  PubMed  Google Scholar 

  38. Keown P, Stiller C, Sinclair NR et al (1983) The clinical relevance of cyclosporine blood levels as measured by radioimmunoassay. Transplant Proc 15:2438–2441

    Google Scholar 

  39. Theng J et al (2002) Distribution of cyclosporin A in the cornea after topical or oral administration. J Ocul Pharmacol Ther 18(1):83–88

    Article  PubMed  CAS  Google Scholar 

  40. Panda A et al (2007) Corneal graft rejection. Surv Ophthalmol 52(4):375–396

    Article  PubMed  Google Scholar 

  41. Mihatsch MJ, Thiel G, Ryffel B (1988) Histopathology of cyclosporine nephrotoxicity. Transplant Proc 20(3 Suppl 3):759–771

    PubMed  CAS  Google Scholar 

  42. Munoz SJ et al (1988) Elevated arterial blood pressure in survivors of liver transplantation treated with cyclosporine and corticosteroids. Transplant Proc 20(3 Suppl 3):623–627

    PubMed  CAS  Google Scholar 

  43. Vine W et al (1988) Cyclosporine-induced hepatotoxicity: a microassay by hepatocytes in tissue culture. Transplant Proc 20(3 Suppl 3):859–862

    PubMed  CAS  Google Scholar 

  44. Boubenider S et al (1997) Incidence and consequences of post-transplantation lymphoproliferative disorders. J Nephrol 10(3):136–145

    PubMed  CAS  Google Scholar 

  45. Kashani S, Mearza AA (2008) Uses and safety profile of ciclosporin in ophthalmology. Expert Opin Drug Saf 7(1):79–89

    Article  PubMed  CAS  Google Scholar 

  46. Rumelt S et al (2002) Systemic cyclosporin A in high failure risk, repeated corneal transplantation. Br J Ophthalmol 86(9):988–992

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Zimmerman TJ (1977) Textbook of ocular pharmacology. Lippincott-Raven, Washington

    Google Scholar 

  48. Lee JJ, Kim MK, Wee WR (2015) Adverse effects of low-dose systemic cyclosporine therapy in high-risk penetrating keratoplasty. Graefes Arch Clin Exp Ophthalmol 253(7):1111–1119

  49. Milani JK et al (1993) Prolongation of corneal allograft survival with liposome-encapsulated cyclosporine in the rat eye. Ophthalmology 100(6):890–896

    Article  PubMed  CAS  Google Scholar 

  50. Gebhardt BM, Varnell ED, Kaufman HE (1995) Cyclosporine in collagen particles: corneal penetration and suppression of allograft rejection. J Ocul Pharmacol Ther 11(4):509–517

    Article  PubMed  CAS  Google Scholar 

  51. Mahlberg K et al (1991) Prevention of experimental corneal allograft rejection in rabbits using cyclosporin-collagen shields. Graefes Arch Clin Exp Ophthalmol 229(1):69–74

    Article  PubMed  CAS  Google Scholar 

  52. Chen YF et al (1990) Cyclosporine-containing collagen shields suppress corneal allograft rejection. Am J Ophthalmol 109(2):132–137

    Article  PubMed  CAS  Google Scholar 

  53. Apel A et al (1995) A subconjunctival degradable implant for cyclosporine delivery in corneal transplant therapy. Curr Eye Res 14(8):659–667

    Article  PubMed  CAS  Google Scholar 

  54. Lee SS et al (2007) A pharmacokinetic and safety evaluation of an episcleral cyclosporine implant for potential use in high-risk keratoplasty rejection. Invest Ophthalmol Vis Sci 48(5):2023–2029

    Article  PubMed  Google Scholar 

  55. Theng JT et al (2003) Pharmacokinetic and toxicity study of an intraocular cyclosporine DDS in the anterior segment of rabbit eyes. Invest Ophthalmol Vis Sci 44(11):4895–4899

    Article  PubMed  Google Scholar 

  56. Jaffe GJ et al (1998) Intravitreal sustained-release cyclosporine in the treatment of experimental uveitis. Ophthalmology 105(1):46–56

    Article  PubMed  CAS  Google Scholar 

  57. Pearson PA et al (1996) Evaluation of a delivery system providing long-term release of cyclosporine. Arch Ophthalmol 114(3):311–317

    Article  PubMed  CAS  Google Scholar 

  58. Salisbury JD, Gebhardt BM (1981) Suppression of corneal allograft rejection by cyclosporin A. Arch Ophthalmol 99(9):1640–1643

    Article  PubMed  CAS  Google Scholar 

  59. Wakefield D, McCluskey P (1991) Cyclosporine: a therapy in inflammatory eye disease. J Ocul Pharmacol 7(3):221–226

    PubMed  CAS  Google Scholar 

  60. Herbort CP et al (1989) Penetrating keratoplasty in the rat: a model for the study of immunosuppressive treatment of graft rejection. Jpn J Ophthalmol 33(2):212–220

    PubMed  CAS  Google Scholar 

  61. Coster DJ et al (1979) Prolonged survival of corneal allografts in rabbits treated with cyclosporin A. Lancet 2(8144):688–689

    Article  PubMed  CAS  Google Scholar 

  62. Hunter PA et al (1982) Corneal graft rejection: a new rabbit model and cyclosporin-A. Br J Ophthalmol 66(5):292–302

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. Hill JC (1986) The use of systemic cyclosporin a in human corneal transplantation: a preliminary report. Doc Ophthalmol 62(4):337–344

    Article  PubMed  CAS  Google Scholar 

  64. Hill JC (1989) The use of cyclosporine in high-risk keratoplasty. Am J Ophthalmol 107(5):506–510

    Article  PubMed  CAS  Google Scholar 

  65. Volker-Dieben HJ, D’Amaro J, Van Slooten H et al (1995) The effect of cyclosporin A on corneal graft survival. In: Zieruth M (ed) Immunology of corneal transplantation, 9th edn. Aeolus Press, Buren

    Google Scholar 

  66. Sundmacher R, Reinhard T, Heering P (1992) Six years’ experience with systemic cyclosporin A prophylaxis in high-risk perforating keratoplasty patients. A retrospective study. Ger J Ophthalmol 1(6):432–436

    PubMed  CAS  Google Scholar 

  67. Maeda N, Hosotani H, Ikeda T et al (1992) Effect of oral cyclosporine in high-risk corneal transplantation. Jpn J Clin Ophthalmol 46(1):1071–6

  68. Yamagami S, OhyaT Tsuru T et al (1994) Effect of cyclosporine following penetrating keratoplasty. Jpn J Clin Ophthalmol 48:763–767

    Google Scholar 

  69. Hill JC (1994) Systemic cyclosporine in high-risk keratoplasty. Short- versus long-term therapy. Ophthalmology 101(1):128–133

    Article  PubMed  CAS  Google Scholar 

  70. Hill JC (1995) Systemic cyclosporine in high-risk keratoplasty: long-term results. Eye (Lond) 9(Pt 4):422–428

    Google Scholar 

  71. Miller K et al (1988) Successful engraftment of high-risk corneal allografts with short-term immunosuppression with cyclosporine. Transplantation 45(3):651–653

    Article  PubMed  CAS  Google Scholar 

  72. Rossa V, Sundmacher R, Heering P (1990) Preventive systemic cyclosporin A in risk keratoplasty. Klin Monbl Augenheilkd 197(6):466–469

    Article  PubMed  CAS  Google Scholar 

  73. Reinhard T, Sundmacher R, Heering P (1996) Systemic ciclosporin A in high-risk keratoplasties. Graefes Arch Clin Exp Ophthalmol 234(Suppl 1):S115–S121

    Article  PubMed  CAS  Google Scholar 

  74. Reinhard T et al (1997) Preventive systemic cyclosporin A after keratoplasty at increased risk for immune reactions as the only elevated risk factor. Ophthalmologe 94(7):496–500

    Article  PubMed  CAS  Google Scholar 

  75. Poon AC et al (2001) Systemic cyclosporin A in high risk penetrating keratoplasties: a case-control study. Br J Ophthalmol 85(12):1464–1469

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Inoue K et al (2000) Long-term effects of topical cyclosporine A treatment after penetrating keratoplasty. Jpn J Ophthalmol 44(3):302–305

    Article  PubMed  CAS  Google Scholar 

  77. Robert PY et al (1997) Treatment with cyclosporin A, with low doses, in high-risk penetrating keratoplasties. A bi-centric study of 90 cases. J Fr Ophtalmol 20(7):507–514

    PubMed  CAS  Google Scholar 

  78. Shimazaki J et al (2011) Prospective, randomized study of the efficacy of systemic cyclosporine in high-risk corneal transplantation. Am J Ophthalmol 152(1):33–39 e1

    Article  PubMed  CAS  Google Scholar 

  79. Homan WP et al (1980) Effect of cyclosporin A upon second-set rejection of rat renal allografts. Transplantation 30(5):354–357

    Article  PubMed  CAS  Google Scholar 

  80. Gratwohl A, Forster I, Speck B (1981) Skin grafts in rabbits with cyclosporin A: absence of induction of tolerance and untoward side effects. Transplantation 31(2):136–138

    Article  PubMed  CAS  Google Scholar 

  81. Hess AD, Esa AH, Colombani PM (1988) Mechanisms of action of cyclosporine: effect on cells of the immune system and on subcellular events in T cell activation. Transplant Proc 20(2 Suppl 2):29–40

    PubMed  CAS  Google Scholar 

  82. Young AL et al (2002) Combined intravenous pulse methylprednisolone and oral cyclosporine A in the treatment of corneal graft rejection: 5-year experience. Eye (Lond) 16(3):304–308

    Article  CAS  Google Scholar 

  83. Lam DS et al (1998) The use of combined intravenous pulse methylprednisolone and oral cyclosporin A in the treatment of corneal graft rejection: a preliminary study. Eye (Lond) 12(Pt 4):615–618

    Article  Google Scholar 

  84. Margreiter R et al (1984) Cyclosporine in the treatment of acute allograft rejection refractory to high-dose methylprednisolone: results of a prospectively randomized trial. Transplant Proc 16(5):1202–1204

    PubMed  CAS  Google Scholar 

  85. Wilson SE, Kaufman HE (1990) Graft failure after penetrating keratoplasty. Surv Ophthalmol 34(5):325–356

    Article  PubMed  CAS  Google Scholar 

  86. Donnenfeld E, Pflugfelder SC (2009) Topical ophthalmic cyclosporine: pharmacology and clinical uses. Surv Ophthalmol 54(3):321–338

    Article  PubMed  Google Scholar 

  87. Koay PY, Lee WH, Figueiredo FC (2005) Opinions on risk factors and management of corneal graft rejection in the United kingdom. Cornea 24(3):292–296

    Article  PubMed  Google Scholar 

  88. Bouchard CS, Cavanagh HD (1994) The high-risk keratoplasty patient–quo vadis? Cornea 13(1):1–3

    Article  PubMed  CAS  Google Scholar 

  89. McDonnell PJ et al (2003) Associations of presbyopia with vision-targeted health-related quality of life. Arch Ophthalmol 121(11):1577–1581

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Moorfields Eye Hospital, 162 City Road, London, EC1V 2PD, UK

    Mohammed Ziaei

  2. Royal Oldham Hopsital, Manchester, OL1 2JH, UK

    Fatemeh Ziaei

  3. Queens Hospital, Essex, RM7 0AG, UK

    Bita Manzouri

Authors
  1. Mohammed Ziaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fatemeh Ziaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bita Manzouri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammed Ziaei.

Ethics declarations

Conflict of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ziaei, M., Ziaei, F. & Manzouri, B. Systemic cyclosporine and corneal transplantation. Int Ophthalmol 36, 139–146 (2016). https://doi.org/10.1007/s10792-015-0137-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10792-015-0137-8

Keywords

Search

Navigation