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Risk Classification and Management of Corneal Grafts, Human Leukocyte Antigen Matching, and Options for Immunosuppression Therapy

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Modern Keratoplasty

Part of the book series: Essentials in Ophthalmology ((ESSENTIALS))

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Abstract

Corneal transplantation is a commonly performed human transplant procedure. In low-risk settings, such as keratoconus and Fuch’s dystrophy, corneal transplantation has a high success rate due to the immune privilege of the cornea. However, immune privilege alone is insufficient to prevent transplant rejection, and failure rates increase in high-risk grafts. Major risk factors for corneal graft rejection include previous herpetic infection, infectious leukoma, chemical burn, trauma, prior transplantation, active inflammation, atopy, and corneal neovascularization, among other risk factors. Mitigation strategies for corneal graft rejection include anti-angiogenic and anti-lymphangiogenic therapies. Topical cyclosporine and tacrolimus are useful adjuncts to traditional therapy with topical steroids in reducing rejection rates and improving graft survival. Systemic cyclosporine, mycophenolate, and tacrolimus are beneficial to graft survival. Current clinical evidence is reviewed. Histocompatibility matching showed initial promise in earlier studies, but success likely varies on access to accurate modern techniques for histocompatibility typing. Earlier studies showed varied success, likely attributable to primitive methods of histocompatibility typing and variation in the quality of immunotyping among centers. Rejection risk factors, histocompatibility matching, and strategies for immunosuppression are reviewed. Mechanisms of corneal graft rejection, including lymphangiogenesis, are discussed.

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References

  1. Williams KA, Brereton HM, Coster DJ. Prospects for genetic modulation of corneal graft survival. Eye (Lond). 2009;23(10):1904–9. https://doi.org/10.1038/eye.2008.378.

    Article  CAS  PubMed  Google Scholar 

  2. Gain P, Jullienne R, He Z, et al. Global survey of corneal transplantation and eye banking. JAMA Ophthalmol. 2016;134(2):167–73. https://doi.org/10.1001/jamaophthalmol.2015.4776.

    Article  PubMed  Google Scholar 

  3. van Essen TH, Roelen DL, Williams KA, Jager MJ. Matching for human leukocyte antigens (HLA) in corneal transplantation – to do or not to do. Prog Retin Eye Res. 2015;46:84–110. https://doi.org/10.1016/j.preteyeres.2015.01.001.

    Article  CAS  PubMed  Google Scholar 

  4. Niederkorn JY, Larkin DFP. Immune privilege of corneal allografts. Ocul Immunol Inflamm. 2010;18(3):162–71. https://doi.org/10.3109/09273948.2010.486100.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Patel SV, Diehl NN, Hodge DO, Bourne WM. Donor risk factors for graft failure in a 20-year study of penetrating keratoplasty. Arch Ophthalmol. 2010;128(4):418–25. https://doi.org/10.1001/archophthalmol.2010.27.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Writing Committee for the Cornea Donor Study Research Group, Sugar A, Gal RL, et al. Factors associated with corneal graft survival in the cornea donor study. JAMA Ophthalmol. 2015;133(3):246–54. https://doi.org/10.1001/jamaophthalmol.2014.3923.

    Article  Google Scholar 

  7. Amescua G, Collings F, Sidani A, et al. Effect of CXCL-1/KC production in high risk vascularized corneal allografts on T cell recruitment and graft rejection. Transplantation. 2008;85(4):615–25. https://doi.org/10.1097/TP.0b013e3181636d9d.

    Article  CAS  PubMed  Google Scholar 

  8. Coster DJ, Williams KA. Management of high-risk corneal grafts. Eye (Lond). 2003;17(8):996–1002. https://doi.org/10.1038/sj.eye.6700634.

    Article  CAS  PubMed  Google Scholar 

  9. Collaborative Corneal Transplantation Studies Research Group. The Collaborative Corneal Transplantation Studies (CCTS): effectiveness of histocompatibility matching in high-risk corneal transplantation. Arch Ophthalmol. 1992;110(10):1392–403. https://doi.org/10.1001/archopht.1992.01080220054021.

    Article  Google Scholar 

  10. Williams KA, Roder D, Esterman A, Muehlberg SM, Coster DJ. Factors predictive of corneal graft survival. Report from the Australian Corneal Graft Registry. Ophthalmology. 1992;99(3):403–14. https://doi.org/10.1016/s0161-6420(92)31960-8.

    Article  CAS  PubMed  Google Scholar 

  11. Thompson RW Jr, Price MO, Bowers PJ, Price FW. Long-term graft survival after penetrating keratoplasty. Ophthalmology. 2003;110(7):1396–402. https://doi.org/10.1016/S0161-6420(03)00463-9.

    Article  PubMed  Google Scholar 

  12. Tourkmani AK, Sánchez-Huerta V, De Wit G, et al. Weighing of risk factors for penetrating keratoplasty graft failure: application of Risk Score System. Int J Ophthalmol. 2017;10(3):372–7. https://doi.org/10.18240/ijo.2017.03.08.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Barraquer RI, Pareja-Aricò L, Gómez-Benlloch A, Michael R. Risk factors for graft failure after penetrating keratoplasty. Medicine. 2019;98(17):e15274. https://doi.org/10.1097/MD.0000000000015274.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Williams KA, Muehlberg SM, Lewis RF, Coster DJ. Long-term outcome in corneal allotransplantation. Transplant Proc. 1997;29(1–2):983. https://doi.org/10.1016/S0041-1345(96)00335-1.

    Article  CAS  PubMed  Google Scholar 

  15. Armitage WJ, Goodchild C, Griffin MD, et al. High-risk corneal transplantation: recent developments and future possibilities. Transplantation. 2019;103(12):2468–78. https://doi.org/10.1097/TP.0000000000002938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Di Zazzo A, Kheirkhah A, Abud TB, Goyal S, Dana R. Management of high-risk corneal transplantation. Surv Ophthalmol. 2017;62(6):816–27. https://doi.org/10.1016/j.survophthal.2016.12.010.

    Article  PubMed  Google Scholar 

  17. Maguire MG, Stark WJ, Gottsch JD, et al. Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies. Collaborative Corneal Transplantation Studies Research Group. Ophthalmology. 1994;101(9):1536–47. https://doi.org/10.1016/s0161-6420(94)31138-9.

    Article  CAS  PubMed  Google Scholar 

  18. Reinhard T, Böhringer D, Sundmacher R. Accelerated chronic endothelial cell loss after penetrating keratoplasty in glaucoma eyes. J Glaucoma. 2001;10(6):446–51. https://doi.org/10.1097/00061198-200112000-00002.

    Article  CAS  PubMed  Google Scholar 

  19. Cho SW, Kim JM, Choi CY, Park KH. Changes in corneal endothelial cell density in patients with normal-tension glaucoma. Jpn J Ophthalmol. 2009;53(6):569–73. https://doi.org/10.1007/s10384-009-0740-1.

    Article  PubMed  Google Scholar 

  20. Gagnon MM, Boisjoly HM, Brunette I, Charest M, Amyot M. Corneal endothelial cell density in glaucoma. Cornea. 1997;16(3):314–8.

    Article  CAS  PubMed  Google Scholar 

  21. Janson BJ, Alward WL, Kwon YH, et al. Glaucoma-associated corneal endothelial cell damage: a review. Surv Ophthalmol. 2018;63(4):500–6. https://doi.org/10.1016/j.survophthal.2017.11.002.

    Article  PubMed  Google Scholar 

  22. Ferreira TB, Ribeiro FJ, Silva D, Matos AC, Gaspar S, Almeida S. Comparison of refractive and visual outcomes of three presbyopia-correcting intraocular lenses. J Cataract Refract Surg. 2022;48(3):280–7. https://doi.org/10.1097/j.jcrs.0000000000000743.

    Article  PubMed  Google Scholar 

  23. Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, Panda-Jonas S. Glaucoma. Lancet. 2017;390(10108):2183–93. https://doi.org/10.1016/S0140-6736(17)31469-1.

    Article  PubMed  Google Scholar 

  24. Chen M-J, Liu CJ-L, Cheng C-Y, Lee S-M. Corneal status in primary angle-closure glaucoma with a history of acute attack. J Glaucoma. 2012;21(1):12–6. https://doi.org/10.1097/IJG.0b013e3181fc800a.

    Article  CAS  PubMed  Google Scholar 

  25. Tan AN, Webers CAB, Berendschot TTJM, et al. Corneal endothelial cell loss after Baerveldt glaucoma drainage device implantation in the anterior chamber. Acta Ophthalmol. 2017;95(1):91–6. https://doi.org/10.1111/aos.13161.

    Article  PubMed  Google Scholar 

  26. Koo EB, Hou J, Han Y, Keenan JD, Stamper RL, Jeng BH. Effect of glaucoma tube shunt parameters on cornea endothelial cells in patients with ahmed valve implants. Cornea. 2015;34(1):37. https://doi.org/10.1097/ICO.0000000000000301.

    Article  PubMed  Google Scholar 

  27. Williams KA, White MA, Ash JK, Coster DJ. Leukocytes in the graft bed associated with corneal graft failure. Analysis by immunohistology and actuarial graft survival. Ophthalmology. 1989;96(1):38–44. https://doi.org/10.1016/s0161-6420(89)32949-6.

    Article  CAS  PubMed  Google Scholar 

  28. Cursiefen C, Maruyama K, Jackson DG, Streilein JW, Kruse FE. Time course of angiogenesis and lymphangiogenesis after brief corneal inflammation. Cornea. 2006;25(4):443. https://doi.org/10.1097/01.ico.0000183485.85636.ff.

    Article  PubMed  Google Scholar 

  29. Goodfellow JFB, Nabili S, Jones MNA, et al. Antiviral treatment following penetrating keratoplasty for herpetic keratitis. Eye. 2011;25(4):470–4. https://doi.org/10.1038/eye.2010.237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Halberstadt M, Machens M, Gahlenbek KA, Böhnke M, Garweg JG. The outcome of corneal grafting in patients with stromal keratitis of herpetic and non-herpetic origin. Br J Ophthalmol. 2002;86(6):646. https://doi.org/10.1136/bjo.86.6.646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gessa-Sorroche M, Kanclerz P, Alio J. Evidence in the prevention of the recurrence of herpes simplex and herpes zoster keratitis after eye surgery. Archivos De La Sociedad Española De Oftalmología Engl Ed. 2022;97(3):149–60. https://doi.org/10.1016/j.oftale.2022.02.003.

    Article  CAS  Google Scholar 

  32. Lee JJ, Kim MK, Wee WR. Adverse effects of low-dose systemic cyclosporine therapy in high-risk penetrating keratoplasty. Graefes Arch Clin Exp Ophthalmol. 2015;253(7):1111–9. https://doi.org/10.1007/s00417-015-3008-0.

    Article  CAS  PubMed  Google Scholar 

  33. Abdelmassih Y, Dubrulle P, Sitbon C, et al. Therapeutic challenges and prognosis of Descemet’s membrane endothelial keratoplasty in herpes simplex eye disease. Cornea. 2019;38(5):553–8. https://doi.org/10.1097/ico.0000000000001891.

    Article  PubMed  Google Scholar 

  34. Tambasco FP, Cohen EJ, Nguyen LH, Rapuano CJ, Laibson PR. oral acyclovir after penetrating keratoplasty for herpes simplex keratitis. Arch Ophthalmol. 1999;117(4):445–9. https://doi.org/10.1001/archopht.117.4.445.

    Article  CAS  PubMed  Google Scholar 

  35. Sterk CC, Jager MJ, Swart M, Berg VD. Recurrent herpetic keratitis in penetrating keratoplasty. Doc Ophthalmol. 1995;90(1):29–33. https://doi.org/10.1007/bf01203291.

    Article  CAS  PubMed  Google Scholar 

  36. Plšková J, Holáň V, Filipec M, Forrester JV. Lymph node removal enhances corneal graft survival in mice at high risk of rejection. BMC Ophthalmol. 2004;4:3.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Küchle M, Cursiefen C, Nguyen NX, et al. Risk factors for corneal allograft rejection: intermediate results of a prospective normal-risk keratoplasty study. Graefes Arch Clin Exp Ophthalmol. 2002;240(7):580–4. https://doi.org/10.1007/s00417-002-0496-5.

    Article  PubMed  Google Scholar 

  38. Nguyen NX, Martus P, Seitz B, Cursiefen C. Atopic dermatitis as a risk factor for graft rejection following normal-risk keratoplasty. Graefes Arch Clin Exp Ophthalmol. 2009;247(4):573–4. https://doi.org/10.1007/s00417-008-0959-4.

    Article  PubMed  Google Scholar 

  39. Watson SL, Tuft SJ, Dart JKG. Patterns of rejection after deep lamellar keratoplasty. Ophthalmology. 2006;113(4):556–60. https://doi.org/10.1016/j.ophtha.2006.01.006.

    Article  PubMed  Google Scholar 

  40. Reinhard T, Möller M, Sundmacher R. Penetrating keratoplasty in patients with atopic dermatitis with and without systemic cyclosporin A. Cornea. 1999;18(6):645–51. https://doi.org/10.1097/00003226-199911000-00003.

    Article  CAS  PubMed  Google Scholar 

  41. Shimmura-Tomita M, Shimmura S, Satake Y, et al. Keratoplasty postoperative treatment update. Cornea. 2013;32:S60. https://doi.org/10.1097/ICO.0b013e3182a2c937.

    Article  PubMed  Google Scholar 

  42. Niederkorn JY, Chen PW, Mellon J, Stevens C, Mayhew E. Allergic airway hyperreactivity increases the risk for corneal allograft rejection. Am J Transplant. 2009;9(5):1017–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Flynn TH, Ohbayashi M, Ikeda Y, Ono SJ, Larkin DF. Effect of allergic conjunctival inflammation on the allogeneic response to donor cornea. Invest Ophthalmol Vis Sci. 2007;48(9):4044–9. https://doi.org/10.1167/iovs.06-0973.

    Article  PubMed  Google Scholar 

  44. Tomita M, Shimmura S, Tsubota K, Shimazaki J. Postkeratoplasty atopic sclerokeratitis in keratoconus patients. Ophthalmology. 2008;115(5):851–6. https://doi.org/10.1016/j.ophtha.2007.07.018.

    Article  PubMed  Google Scholar 

  45. Lyons CJ, Dart JKG, Aclimandos WA, Lightman S, Buckley RJ. Sclerokeratitis after keratoplasty in atopy. Ophthalmology. 1990;97(6):729–33. https://doi.org/10.1016/S0161-6420(90)32523-X.

    Article  CAS  PubMed  Google Scholar 

  46. Jayaram H, Falcon MG. Atopic rhinitis: a risk factor for spontaneous wound dehiscence following removal of a continuous penetrating keratoplasty suture. Graefes Arch Clin Exp Ophthalmol. 2005;243(9):958–9. https://doi.org/10.1007/s00417-005-1136-7.

    Article  PubMed  Google Scholar 

  47. Ghoraishi M, Akova YA, Tugal-Tutkun I, Foster CS. Penetrating keratoplasty in atopic keratoconjunctivitis. Cornea. 1995;14(6):610–3.

    Article  CAS  PubMed  Google Scholar 

  48. Geggel HS. Successful penetrating keratoplasty in a patient with severe atopic keratoconjunctivitis and elevated serum IgE level treated with long-term topical cyclosporin A. Cornea. 1994;13(6):543.

    Article  CAS  PubMed  Google Scholar 

  49. Solomon A, Ellies P, Anderson DF, et al. Long-term outcome of keratolimbal allograft with or without penetrating keratoplasty for total limbal stem cell deficiency. Ophthalmology. 2002;109(6):1159–66.

    Article  PubMed  Google Scholar 

  50. Atallah MR, Palioura S, Perez VL, Amescua G. Limbal stem cell transplantation: current perspectives. Clin Ophthalmol. 2016;10:593–602. https://doi.org/10.2147/OPTH.S83676.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Ozer MD, Altinkurt E, Alparslan N. The long-term surgical outcomes of conjunctival-limbal autograft procedure with or without penetrating keratoplasty in eyes with unilateral limbal stem cell deficiency. Taiwan J Ophthalmol. 2020;10(1):22–8. https://doi.org/10.4103/tjo.tjo_55_19.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Krysik K, Dobrowolski D, Tarnawska D, Wylegala E, Lyssek-Boroń A. Long-term outcomes of allogeneic ocular surface reconstruction: keratolimbal allograft (KLAL) followed by penetrating keratoplasty (PK). J Ophthalmol. 2020;2020:5189179. https://doi.org/10.1155/2020/5189179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Solomon A, Pires RT, Tseng SC. Amniotic membrane transplantation after extensive removal of primary and recurrent pterygia. Ophthalmology. 2001;108(3):449–60. https://doi.org/10.1016/s0161-6420(00)00567-4.

    Article  CAS  PubMed  Google Scholar 

  54. Daya SM, Ilari FA. Living related conjunctival limbal allograft for the treatment of stem cell deficiency. Ophthalmology. 2001;108(1):126–33. https://doi.org/10.1016/s0161-6420(00)00475-9; discussion 133–4.

    Article  CAS  PubMed  Google Scholar 

  55. Cursiefen C, Chen L, Dana MR, Streilein JW. Corneal lymphangiogenesis: evidence, mechanisms, and implications for corneal transplant immunology. Cornea. 2003;22(3):273.

    Article  PubMed  Google Scholar 

  56. Yamagami S, Dana MR. The critical role of lymph nodes in corneal alloimmunization and graft rejection. Invest Ophthalmol Vis Sci. 2001;42(6):1293–8.

    CAS  PubMed  Google Scholar 

  57. Bahar I, Kaiserman I, McAllum P, Rootman D, Slomovic A. Subconjunctival bevacizumab injection for corneal neovascularization in recurrent pterygium. Curr Eye Res. 2009. https://doi.org/10.1080/02713680701799101.

  58. Kim SW, Ha BJ, Kim EK, Tchah H, Kim T-I. The effect of topical bevacizumab on corneal neovascularization. Ophthalmology. 2008;115(6):e33–8. https://doi.org/10.1016/j.ophtha.2008.02.013.

    Article  PubMed  Google Scholar 

  59. Bachmann BO, Bock F, Wiegand SJ, et al. Promotion of graft survival by vascular endothelial growth factor a neutralization after high-risk corneal transplantation. Arch Ophthalmol. 2008;126(1):71–7. https://doi.org/10.1001/archopht.126.1.71.

    Article  PubMed  Google Scholar 

  60. Chen L, Hamrah P, Cursiefen C, et al. Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Nat Med. 2004;10(8):813–5. https://doi.org/10.1038/nm1078.

    Article  CAS  PubMed  Google Scholar 

  61. Zhang W, Schönberg A, Hamdorf M, Georgiev T, Cursiefen C, Bock F. Preincubation of donor tissue with a VEGF cytokine trap promotes subsequent high-risk corneal transplant survival. Br J Ophthalmol. 2022;106(11):1617–26. https://doi.org/10.1136/bjophthalmol-2021-319745.

    Article  PubMed  Google Scholar 

  62. Su W, Sun S, Tian B, et al. Efficacious, safe, and stable inhibition of corneal neovascularization by AAV-vectored anti-VEGF therapeutics. Mol Ther Methods Clin Dev. 2021;22:107–21. https://doi.org/10.1016/j.omtm.2021.06.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Salabarria A-C, Braun G, Heykants M, et al. Local VEGF-A blockade modulates the microenvironment of the corneal graft bed. Am J Transplant. 2019;19(9):2446–56. https://doi.org/10.1111/ajt.15331.

    Article  CAS  PubMed  Google Scholar 

  64. Dohlman TH, Omoto M, Hua J, et al. VEGF-trap aflibercept significantly improves long-term graft survival in high-risk corneal transplantation. Transplantation. 2015;99(4):678–86. https://doi.org/10.1097/TP.0000000000000512.

    Article  CAS  PubMed  Google Scholar 

  65. Fasciani R, Crincoli E, Mosca L, Guccione L, Caristia A, Rizzo S. Role of pre-transplant corneal injective anti VEGF treatment in high risk transplantation corneas. 2021. https://doi.org/10.21203/rs.3.rs-246503/v1.

  66. Stodola E. Applications for bevacizumab in corneal surgery. EyeWorld. 2021.

    Google Scholar 

  67. Opelz G, Döhler B. Effect of human leukocyte antigen compatibility on kidney graft survival: comparative analysis of two decades. Transplantation. 2007;84(2):137–43. https://doi.org/10.1097/01.tp.0000269725.74189.b9.

    Article  CAS  PubMed  Google Scholar 

  68. Loupy A, Hill GS, Jordan SC. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol. 2012;8(6):348–57. https://doi.org/10.1038/nrneph.2012.81.

    Article  CAS  PubMed  Google Scholar 

  69. Hopkins KA, Maguire MG, Fink NE, Bias WB. Reproducibility of HLA-A, B, and DR typing using peripheral blood samples: results of retyping in the collaborative corneal transplantation studies. Collaborative Corneal Transplantation Studies Group (corrected). Hum Immunol. 1992;33(2):122–8. https://doi.org/10.1016/0198-8859(92)90062-r.

    Article  CAS  PubMed  Google Scholar 

  70. Vail A, Gore SM, Bradley BA, Easty DL, Rogers CA, Armitage WJ. Conclusions of the corneal transplant follow up study. Collaborating Surgeons. Br J Ophthalmol. 1997;81(8):631–6. https://doi.org/10.1136/bjo.81.8.631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Völker-Dieben HJ, Claas FH, Schreuder GM, et al. Beneficial effect of HLA-DR matching on the survival of corneal allografts. Transplantation. 2000;70(4):640–8. https://doi.org/10.1097/00007890-200008270-00018.

    Article  PubMed  Google Scholar 

  72. Sundmacher R, editor. Adequate HLA matching in keratoplasty. Dusseldorf: Karger Medical and Scientific Publishers; 2003.

    Google Scholar 

  73. Völker-Dieben HJ, Schreuder GMT, Claas FHJ, et al. Histocompatibility and corneal transplantation. Dev Ophthalmol. 2003;36:22–41. https://doi.org/10.1159/000067653.

    Article  PubMed  Google Scholar 

  74. Kwitko S, Marinho D, Barcaro S, et al. Allograft conjunctival transplantation for bilateral ocular surface disorders. Ophthalmology. 1995;102(7):1020–5. https://doi.org/10.1016/s0161-6420(95)30918-9.

    Article  CAS  PubMed  Google Scholar 

  75. Armitage WJ, Winton HL, Jones MNA, et al. Corneal transplant follow-up study II (CTFS II): a prospective clinical trial to determine the influence of HLA class II matching on corneal transplant rejection: baseline donor and recipient characteristics. Br J Ophthalmol. 2019;103(1):132–6. https://doi.org/10.1136/bjophthalmol-2017-311342.

    Article  PubMed  Google Scholar 

  76. Böhringer D, Spierings E, Enczmann J, et al. Matching of the minor histocompatibility antigen HLA-A1/H-Y may improve prognosis in corneal transplantation. Transplantation. 2006;82(8):1037–41. https://doi.org/10.1097/01.tp.0000235908.54766.44.

    Article  CAS  PubMed  Google Scholar 

  77. Hopkinson CL, Romano V, Kaye RA, et al. The influence of donor and recipient gender incompatibility on corneal transplant rejection and failure. Am J Transplant. 2017;17(1):210–7. https://doi.org/10.1111/ajt.13926.

    Article  CAS  PubMed  Google Scholar 

  78. Böhringer D, Reinhard T, Böhringer S, Enczmann J, Godehard E, Sundmacher R. Predicting time on the waiting list for HLA matched corneal grafts. Tissue Antigens. 2002;59(5):407–11. https://doi.org/10.1034/j.1399-0039.2002.590507.x.

    Article  PubMed  Google Scholar 

  79. Alió Del Barrio JL, et al. Corneal transplantation after failed grafts: options and outcomes. Surv Ophthalmol. 2021;66(1):20–40. https://doi.org/10.1016/j.survophthal.2020.10.003.

    Article  PubMed  Google Scholar 

  80. Duquesnoy RJ, Askar M. HLAMatchmaker: a molecularly based algorithm for histocompatibility determination. V. Eplet matching for HLA-DR, HLA-DQ, and HLA-DP. Hum Immunol. 2007;68(1):12–25. https://doi.org/10.1016/j.humimm.2006.10.003.

    Article  CAS  PubMed  Google Scholar 

  81. Böhringer D, Sundmacher R, Reinhard T. Histocompatilibility matching in penetrating keratoplasty. In: Reinhard T, Larkin F, Larkin DFP, editors. Cornea and external eye disease. Berlin: Springer; 2006. https://books.google.com/books/about/Cornea_and_External_Eye_Disease.html?id=uAfeQjUKTf4C.

    Google Scholar 

  82. Shimazaki J, Iseda A, Satake Y, Shimazaki-Den S. Efficacy and safety of long-term corticosteroid eye drops after penetrating keratoplasty: a prospective, randomized, clinical trial. Ophthalmology. 2012;119(4):668–73. https://doi.org/10.1016/j.ophtha.2011.10.016.

    Article  PubMed  Google Scholar 

  83. Kharod-Dholakia B, Randleman JB, Bromley JG, Stulting RD. Prevention and treatment of corneal graft rejection: current practice patterns of the Cornea Society (2011). Cornea. 2015;34(6):609. https://doi.org/10.1097/ICO.0000000000000403.

    Article  PubMed  Google Scholar 

  84. Nguyen NX, Seitz B, Martus P, Langenbucher A, Cursiefen C. Long-term topical steroid treatment improves graft survival following normal-risk penetrating keratoplasty. Am J Ophthalmol. 2007;144(2):318–9. https://doi.org/10.1016/j.ajo.2007.03.028.

    Article  CAS  PubMed  Google Scholar 

  85. Ross AH, Jones MNA, Nguyen DQ, et al. Long-term topical steroid treatment after penetrating keratoplasty in patients with pseudophakic bullous keratopathy. Ophthalmology. 2009;116(12):2369–72. https://doi.org/10.1016/j.ophtha.2009.06.006.

    Article  PubMed  Google Scholar 

  86. Butcher JM, Austin M, McGalliard J, Bourke RD. Bilateral cataracts and glaucoma induced by long term use of steroid eye drops. BMJ. 1994;309(6946):43. https://doi.org/10.1136/bmj.309.6946.43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Marques RE, Leal I, Guerra PS, Barão RC, Quintas AM, Rodrigues W. Topical corticosteroids with topical cyclosporine A versus topical corticosteroids alone for immunological corneal graft rejection. Eur J Ophthalmol. 2022;32(3):1469–81. https://doi.org/10.1177/11206721211023320.

    Article  PubMed  Google Scholar 

  88. Donnenfeld E, Pflugfelder SC. Topical ophthalmic cyclosporine: pharmacology and clinical uses. Surv Ophthalmol. 2009;54(3):321–38. https://doi.org/10.1016/j.survophthal.2009.02.002.

    Article  PubMed  Google Scholar 

  89. Javadi MA, Feizi S, Karbasian A, Rastegarpour A. Efficacy of topical ciclosporin A for treatment and prevention of graft rejection in corneal grafts with previous rejection episodes. Br J Ophthalmol. 2010;94(11):1464–7. https://doi.org/10.1136/bjo.2009.172577.

    Article  CAS  PubMed  Google Scholar 

  90. Ünal M, Yücel I. Evaluation of topical ciclosporin 0.05% for prevention of rejection in high-risk corneal grafts. Br J Ophthalmol. 2008;92(10):1411–4. https://doi.org/10.1136/bjo.2008.143024.

    Article  PubMed  Google Scholar 

  91. Poon A, Constantinou M, Lamoureux E, Taylor HR. Topical cyclosporin A in the treatment of acute graft rejection: a randomized controlled trial. Clin Experiment Ophthalmol. 2008;36(5):415–21. https://doi.org/10.1111/j.1442-9071.2008.01808.x.

    Article  PubMed  Google Scholar 

  92. Sinha R, Jhanji V, Verma K, Sharma N, Biswas NR, Vajpayee RB. Efficacy of topical cyclosporine A 2% in prevention of graft rejection in high-risk keratoplasty: a randomized controlled trial. Graefes Arch Clin Exp Ophthalmol. 2010;248(8):1167–72. https://doi.org/10.1007/s00417-010-1388-8.

    Article  CAS  PubMed  Google Scholar 

  93. Shoughy SS. Topical tacrolimus in anterior segment inflammatory disorders. Eye Vis (Lond). 2017;4(1):1–7. https://doi.org/10.1186/s40662-017-0072-z.

    Article  Google Scholar 

  94. Turgut B, Guler M, Akpolat N, Demır T, Celıker U. The impact of tacrolimus on vascular endothelial growth factor in experimental corneal neovascularization. Curr Eye Res. 2011;36(1):34–40. https://doi.org/10.3109/02713683.2010.516620.

    Article  CAS  PubMed  Google Scholar 

  95. Shoughy SS, Aljassar FM, Tabbara KF. Aqueous penetration of topical tacrolimus. Am J Ophthalmol Case Rep. 2020;17:100582. https://doi.org/10.1016/j.ajoc.2019.100582.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Taddio A, Cimaz R, Caputo R, et al. Childhood chronic anterior uveitis associated with vernal keratoconjunctivitis (VKC): successful treatment with topical tacrolimus. Case series. Pediatr Rheumatol Online J. 2011;9(1):34. https://doi.org/10.1186/1546-0096-9-34.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Kheirkhah A, Zavareh MK, Farzbod F, Mahbod M, Behrouz MJ. Topical 0.005% tacrolimus eye drop for refractory vernal keratoconjunctivitis. Eye (Lond). 2011;25(7):872–80. https://doi.org/10.1038/eye.2011.75.

    Article  CAS  PubMed  Google Scholar 

  98. Miyazaki D, Fukushima A, Ohashi Y, et al. Steroid-sparing effect of 0.1% tacrolimus eye drop for treatment of shield ulcer and corneal epitheliopathy in refractory allergic ocular diseases. Ophthalmology. 2017;124(3):287–94. https://doi.org/10.1016/j.ophtha.2016.11.002.

    Article  PubMed  Google Scholar 

  99. Lee YJ, Kim SW, Seo KY. Application for tacrolimus ointment in treating refractory inflammatory ocular surface diseases. Am J Ophthalmol. 2013;155(5):804–13. https://doi.org/10.1016/j.ajo.2012.12.009.

    Article  CAS  PubMed  Google Scholar 

  100. Moscovici BK, Holzchuh R, Chiacchio BB, Santo RM, Shimazaki J, Hida RY. Clinical treatment of dry eye using 0.03% tacrolimus eye drops. Cornea. 2012;31(8):945–9. https://doi.org/10.1097/ICO.0b013e31823f8c9b.

    Article  PubMed  Google Scholar 

  101. Moscovici BK, Holzchuh R, Sakassegawa-Naves FE, et al. Treatment of Sjögren’s syndrome dry eye using 0.03% tacrolimus eye drop: prospective double-blind randomized study. Cont Lens Anterior Eye. 2015;38(5):373–8. https://doi.org/10.1016/j.clae.2015.04.004.

    Article  PubMed  Google Scholar 

  102. Abud TB, Di Zazzo A, Kheirkhah A, Dana R. Systemic immunomodulatory strategies in high-risk corneal transplantation. J Ophthalmic Vis Res. 2017;12(1):81–92. https://doi.org/10.4103/2008-322X.200156.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Durazzo TS, Frencher S, Gusberg R. Influence of race on the management of lower extremity ischemia: revascularization vs amputation. JAMA Surg. 2013;148(7):617–23. https://doi.org/10.1001/jamasurg.2013.1436.

    Article  PubMed  Google Scholar 

  104. Jung JW, Lee YJ, Yoon SC, Kim T-I, Kim EK, Seo KY. Long-term result of maintenance treatment with tacrolimus ointment in chronic ocular graft-versus-host disease. Am J Ophthalmol. 2015;159(3):519–27.e1. https://doi.org/10.1016/j.ajo.2014.11.035.

    Article  CAS  PubMed  Google Scholar 

  105. Dhaliwal JS, Mason BF, Kaufman SC. Long-term use of topical tacrolimus (FK506) in high-risk penetrating keratoplasty. Cornea. 2008;27(4):488. https://doi.org/10.1097/ICO.0b013e3181606086.

    Article  PubMed  Google Scholar 

  106. Magalhaes OA, Marinho DR, Kwitko S. Topical 0.03% tacrolimus preventing rejection in high-risk corneal transplantation: a cohort study. Br J Ophthalmol. 2013;97(11):1395–8. https://doi.org/10.1136/bjophthalmol-2013-303639.

    Article  PubMed  Google Scholar 

  107. Zhai L-Y, Zhang X-R, Liu H, Ma Y, Xu H-C. Observation of topical tacrolimus on high-risk penetrating keratoplasty patients: a randomized clinical trial study. Eye (Lond). 2020;34(9):1600–7. https://doi.org/10.1038/s41433-019-0717-3.

    Article  CAS  PubMed  Google Scholar 

  108. Faramarzi A, Abbasi H, Feizi S, et al. Topical 0.03% tacrolimus versus systemic mycophenolate mofetil as adjuncts to systemic corticosteroids for preventing graft rejection after repeat keratoplasty: one-year results of a randomized clinical trial. Eye (Lond). 2021;35(10):2879–88. https://doi.org/10.1038/s41433-020-01375-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hill JC. The use of cyclosporine in high-risk keratoplasty. Am J Ophthalmol. 1989;107(5):506–10. https://doi.org/10.1016/0002-9394(89)90494-7.

    Article  CAS  PubMed  Google Scholar 

  110. Hill JC. Systemic cyclosporine in high-risk keratoplasty: short- versus long-term therapy. Ophthalmology. 1994;101(1):128–33. https://doi.org/10.1016/S0161-6420(13)31253-6.

    Article  CAS  PubMed  Google Scholar 

  111. Algros M-P, Angonin R, Delbosc B, Cahn J-Y, Kantelip B. Danger of systemic cyclosporine for corneal graft. Cornea. 2002;21(6):613.

    Article  PubMed  Google Scholar 

  112. Abudou M, Wu T, Evans JR, Chen X. Immunosuppressants for the prophylaxis of corneal graft rejection after penetrating keratoplasty. Cochrane Database Syst Rev. 2015;(8):CD007603. https://doi.org/10.1002/14651858.CD007603.pub2.

  113. Bali S, Filek R, Si F, Hodge W. Systemic immunosuppression in high-risk penetrating keratoplasty: a systematic review. J Clin Med Res. 2016;8(4):269–76. https://doi.org/10.14740/jocmr2326w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Den S, Omoto M, Shimmura S, Tsubota K, Shimazaki J. Prospective, randomized study on efficacy of systemic cyclosporine a in high–risk corneal transplantation. Invest Ophthalmol Vis Sci. 2006;47(13):1286.

    Google Scholar 

  115. Shimazaki J, Den S, Omoto M, Satake Y, Shimmura S, Tsubota K. Prospective, randomized study of the efficacy of systemic cyclosporine in high-risk corneal transplantation. Am J Ophthalmol. 2011;152(1):33–39.e1. https://doi.org/10.1016/j.ajo.2011.01.019.

    Article  CAS  PubMed  Google Scholar 

  116. Reinhard T, Mayweg S, Sokolovska Y, et al. Systemic mycophenolate mofetil avoids immune reactions in penetrating high-risk keratoplasty: preliminary results of an ongoing prospectively randomized multicentre study. Transpl Int. 2005;18(6):703–8. https://doi.org/10.1111/j.1432-2277.2005.00126.x.

    Article  CAS  PubMed  Google Scholar 

  117. Reinhard T, Reis A, Böhringer D, et al. Systemic mycophenolate mofetil in comparison with systemic cyclosporin A in high-risk keratoplasty patients: 3 years’ results of a randomized prospective clinical trial. Graefes Arch Clin Exp Ophthalmol. 2001;239(5):367–72. https://doi.org/10.1007/s004170100285.

    Article  CAS  PubMed  Google Scholar 

  118. Birnbaum F, Böhringer D, Sokolovska Y, Sundmacher R, Reinhard T. Immunosuppression with cyclosporine A and mycophenolate mofetil after penetrating high-risk keratoplasty: a retrospective study. Transplantation. 2005;79(8):964. https://doi.org/10.1097/01.TP.0000158022.62059.F2.

    Article  CAS  PubMed  Google Scholar 

  119. Birnbaum F, Mayweg S, Reis A, et al. Mycophenolate mofetil (MMF) following penetrating high-risk keratoplasty: long-term results of a prospective, randomised, multicentre study. Eye (Lond). 2009;23(11):2063–70. https://doi.org/10.1038/eye.2008.402.

    Article  CAS  PubMed  Google Scholar 

  120. Mayer K, Reinhard T, Reis A, Voiculescu A, Sundmacher R. Synergistic antiherpetic effect of acyclovir and mycophenolate mofetil following keratoplasty in patients with herpetic eye disease: first results of a randomised pilot study. Graefes Arch Clin Exp Ophthalmol. 2003;241(12):1051–4. https://doi.org/10.1007/s00417-003-0724-7.

    Article  CAS  PubMed  Google Scholar 

  121. Reis A, Reinhard T, Voiculescu A, et al. Mycophenolate mofetil versus cyclosporin A in high risk keratoplasty patients: a prospectively randomised clinical trial. Br J Ophthalmol. 1999;83(11):1268–71. https://doi.org/10.1136/bjo.83.11.1268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the management of high-risk corneal and limbal grafts. Ophthalmology. 2001;108(10):1838–44. https://doi.org/10.1016/s0161-6420(01)00759-x.

    Article  CAS  PubMed  Google Scholar 

  123. Holland EJ, Mogilishetty G, Skeens HM, et al. Systemic immunosuppression in ocular surface stem cell transplantation: results of a 10-year experience. Cornea. 2012;31(6):655. https://doi.org/10.1097/ICO.0b013e31823f8b0c.

    Article  PubMed  Google Scholar 

  124. Baradaran-Rafii A, Eslani M, Djalillian AR. Complications of keratolimbal allograft surgery. Cornea. 2013;32(5):561. https://doi.org/10.1097/ICO.0b013e31826215eb.

    Article  PubMed  Google Scholar 

  125. Holland EJ. Living related conjunctival limbal allograft for the treatment of stem cell deficiency - discussion. Ophthalmology. 2001;108(1):133–4.

    Article  CAS  PubMed  Google Scholar 

  126. Chan CC, Holland EJ. Keratolimbal allograft. In: Mannis MJ, Holland EJ, editors. Cornea. 5th ed. New York: Elsevier; 2022.

    Google Scholar 

  127. Shanbhag SS, Patel CN, Goyal R, Donthineni PR, Singh V, Basu S. Simple limbal epithelial transplantation (SLET): review of indications, surgical technique, mechanism, outcomes, limitations, and impact. Indian J Ophthalmol. 2019;67(8):1265–77. https://doi.org/10.4103/ijo.ijo_117_19.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Iyer G, Srinivasan B, Agarwal S, Tarigopula A. Outcome of allo simple limbal epithelial transplantation (alloSLET) in the early stage of ocular chemical injury. Br J Ophthalmol. 2017;101(6):828–33. https://doi.org/10.1136/bjophthalmol-2016-309045.

    Article  PubMed  Google Scholar 

  129. Kaur A, Jamil Z, Priyadarshini SR. Allogeneic simple limbal epithelial transplantation: an appropriate treatment for bilateral stem cell deficiency. BMJ Case Rep. 2021;14(2):e239998. https://doi.org/10.1136/bcr-2020-239998.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Férnandez-Buenaga R, Aiello F, Zaher SS, Grixti A, Ahmad S. Twenty years of limbal epithelial therapy: an update on managing limbal stem cell deficiency. BMJ Open Ophthalmol. 2018;3(1):e000164. https://doi.org/10.1136/bmjophth-2018-000164.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Serna-Ojeda JC, Basu S, Vazirani J, Garfias Y, Sangwan VS. Systemic immunosuppression for limbal allograft and allogenic limbal epithelial cell transplantation. Med Hypothesis Discov Innov Ophthalmol J. 2019;9(1):23–32.

    Google Scholar 

  132. Graue-Hernandez EO. Simple limbal epithelial transplantation. In: Mannis MJ, Holland EJ, editors. Cornea. New York: Elsevier; 2022. p. 1634.e1–e1638.

    Google Scholar 

  133. Daya SM, Watson A, Sharpe JR, et al. Outcomes and DNA analysis of ex vivo expanded stem cell allograft for ocular surface reconstruction. Ophthalmology. 2005;112(3):470–7. https://doi.org/10.1016/j.ophtha.2004.09.023.

    Article  PubMed  Google Scholar 

  134. Eslani M, Cheung AY, Holland EJ. 3-s2.0-B9780323672405001645?indexOverride=GLOBAL. In: Mannis MJ, Holland EJ, editors. Cornea, 5th ed. New York: Elsevier; 2022. p. 1607.e1–14.e1.

    Google Scholar 

  135. Basu S, Sureka SP, Shanbhag SS, Kethiri AR, Singh V, Sangwan VS. Simple limbal epithelial transplantation: long-term clinical outcomes in 125 cases of unilateral chronic ocular surface burns. Ophthalmology. 2016;123(5):1000–10. https://doi.org/10.1016/j.ophtha.2015.12.042.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA

    Paula W. Feng & Guillermo Amescua

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  1. Paula W. Feng
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  2. Guillermo Amescua
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Correspondence to Guillermo Amescua .

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Editors and Affiliations

  1. Vissum Miranza, Miguel Hernández University, Alicante, Spain

    Jorge L. Alió

  2. Vissum-Instituto Oftalmologico de Alica, Miguel Hernandez University, Alicante, Alicante, Spain

    Jorge L. Alió del Barrio

Electronic Supplementary Material

A 35-year-old female sustained a severe chemical burn to both eyes, which was severe in the right eye and mild in the left eye, causing right eye limbal stem cell deficiency, corneal opacification with a vascular pannus, and symblepharon formation, as shown. Simple limbal epithelial transportation (SLET) was performed using a donor allograft from her monozygotic twin. The limbal cells were harvested the same morning. The vascular pannus was removed with forceps and scissors, a permitomy was performed, the cornea was polished with a diamond burr, the symblepharon was repaired with a bulbar conjunctival allograft from her fellow eye, and standard technique was used for SLET. Amniotic membrane was secured to the eye stromal side down with fibrin glue, small pieces of limbal epithelial cells were transferred from the allograft to the cornea on top of the amniotic membrane, the cells were glued in place, and a bandage contact lens was placed. No immunosuppression was required as the cells were from a monozygotic twin (MP4 155695 kb)

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Feng, P.W., Amescua, G. (2023). Risk Classification and Management of Corneal Grafts, Human Leukocyte Antigen Matching, and Options for Immunosuppression Therapy. In: Alió, J.L., del Barrio, J.L.A. (eds) Modern Keratoplasty. Essentials in Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-031-32408-6_3

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