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Pathophysiology of Corneal Graft Rejection

  • Victor L. Perez
  • William Foulsham
  • Kristen Peterson
  • Reza DanaEmail author
Chapter

Abstract

The cornea is the most frequently transplanted tissue in the human body. The primary cause of corneal graft failure is immune rejection, a highly complex sequence of innate and adaptive immune responses that interact to promote tissue destruction. As our understanding of the effector pathways that drive allograft rejection has deepened, so too has our comprehension of the diverse immunoregulatory mechanisms that restrain the effector response and promote graft tolerance. This chapter reviews the incidence, the risk factors and the cellular and molecular mechanisms that underlie corneal allograft rejection. The amalgam of anatomical features, immune cells, and immunoregulatory factors that promote tolerance and immune quiescence are described. Finally, possibilities for future therapeutic approaches to promote graft survival are considered.

Keywords

Corneal transplantation Allograft rejection Antigen presenting cells Regulatory T cells Immune tolerance 

References

  1. 1.
    Bohigian GM, Estes EH, Friedlander IR, Kennedy WR, Moxley JH, Numann PJ, Salva PS, Scott WC, Skom JH, Steinhilber RM, Strong JP, Wagner HN, Braun WE, Deodhar S, Millard CE, Payne V, Richard GA, Shumway NE, Starzl TE, et al. Report of the organ transplant panel. JAMA. 1988;259:719.  https://doi.org/10.1001/jama.1988.03720050055023.CrossRefGoogle Scholar
  2. 2.
    Niederkorn JY. Immunology and immunomodulation of corneal transplantation. Int Rev Immunol. 2002;21:173–96.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Khodadoust AA. The allograft rejection reaction: the leading cause of late failure of clinical corneal grafts, Wiley; 2008, p. 151–167. doi: https://doi.org/10.1002/9780470719985.ch9.CrossRefGoogle Scholar
  4. 4.
    Arentsen JJ. Corneal transplant allograft reaction: possible predisposing factors. Trans Am OphthalmolSoc. 1983;81:361–402.Google Scholar
  5. 5.
    The Collaborative Corneal Transplantation Studies Research Group. Effectiveness of histocompatibility matching in high-risk corneal trasplantation. Arch Ophthalmol. 1992;110:1392.  https://doi.org/10.1001/archopht.1992.01080220054021.CrossRefGoogle Scholar
  6. 6.
    Maguire MG, Stark WJ, Gottsch JD, Stulting RD, Sugar A, Fink NE, Schwartz A. Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies. Ophthalmology. 1994;101:1536–47.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hill JC. Systemic cyclosporine in high-risk keratoplasty: long-term results. Eye. 1995;9:422–8.  https://doi.org/10.1038/eye.1995.99.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Coster DJ, Williams KA. Management of high-risk corneal grafts. Eye. 2003;17:996–1002.  https://doi.org/10.1038/sj.eye.6700634.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Tan Y, Abdulreda MH, Cruz-Guilloty F, Cutrufello N, Shishido A, Martinez RE, Duffort S, Xia X, Echegaray-Mendez J, Levy RB, Berggren P-O, Perez VL. Role of T cell recruitment and chemokine-regulated intra-graft T cell motility patterns in corneal allograft rejection. Am J Transplant. 2013;13:1461–73.  https://doi.org/10.1111/ajt.12228.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Rosenberg AS, Singer A. Cellular basis of skin allograft rejection: an in vivo model of immune-mediated tissue destruction. Annu Rev Immunol. 1992;10:333–58.  https://doi.org/10.1146/annurev.iy.10.040192.002001.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Hall BM. Cells mediating allograft rejection. Transplantation. 1991;51:1141–51.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Beauregard C, Huq SO, Barabino S, Zhang Q, Kazlauskas A, Dana MR. Keratocyteapoptosis and failure of corneal allografts. Transplantation. 2006;81:1577–82.  https://doi.org/10.1097/01.tp.0000209503.62204.c3.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Glasser DB. Changing trends in keratoplasty. Am J Ophthalmol. 2011;151:394–6.  https://doi.org/10.1016/j.ajo.2010.11.012.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Nanavaty MA, Wang X, Shortt AJ. Endothelial keratoplasty versus penetrating keratoplasty for Fuchs endothelial dystrophy. Cochrane Database Syst Rev. 2014:CD008420.  https://doi.org/10.1002/14651858.CD008420.pub3.
  15. 15.
    Price FW, Feng MT, Price MO. Evolution of endothelial keratoplasty. Cornea. 2015;34:S41–7.  https://doi.org/10.1097/ICO.0000000000000505.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ang M, Wilkins MR, Mehta JS, Tan D. Descemet membrane endothelial keratoplasty. Br J Ophthalmol. 2016;100:15–21.  https://doi.org/10.1136/bjophthalmol-2015-306837.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Price MO, Price FW Jr. Endothelial keratoplasty– a review. ClinExpOphthalmol. 2010;38:128–40.  https://doi.org/10.1111/j.1442-9071.2010.02213.x.CrossRefGoogle Scholar
  18. 18.
    Keane MC, Galettis RA, Mills RAD, Coster DJ, Williams KA. For contributors to the Australian corneal graft registry. A comparison of endothelial and penetrating keratoplasty outcomes following failed penetrating keratoplasty: a registry study. Br J Ophthalmol. 2016;100:1569–75.  https://doi.org/10.1136/bjophthalmol-2015-307792.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Coster DJ, Lowe MT, Keane MC, Williams KA, Australian Corneal Graft Registry Contributors. A comparison of lamellar and penetrating keratoplastyoutcomes. Ophthalmology. 2014;121:979–87.  https://doi.org/10.1016/j.ophtha.2013.12.017.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Patten JT, Cavanagh HD, Pavan-Langston D. Penetrating keratoplasty in acute herpetic corneal performations. Ann Ophthalmol. 1976;8:287–94.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Murphy SP, Porrett PM, Turka LA. Innate immunity in transplant tolerance and rejection. Immunol Rev. 2011;241:39–48.  https://doi.org/10.1111/j.1600-065X.2011.01009.x.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Amouzegar A, Chauhan SK, Dana R. Alloimmunity and tolerance in corneal transplantation. J Immunol. 2016;196:3983–91.  https://doi.org/10.4049/jimmunol.1600251.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Amouzegar A, Chauhan SK. Effector and regulatory T cell trafficking in corneal allograft rejection. MediatInflamm. 2017;2017:8670280.  https://doi.org/10.1155/2017/8670280.CrossRefGoogle Scholar
  24. 24.
    Foulsham W, Coco G, Amouzegar A, Chauhan SK, Dana R. When clarity is crucial: regulating ocular surface immunity. Trends Immunol. 2018;39:288–301.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Yamada J, Kurimoto I, Streilein JW. Role of CD4+ T cells in immunobiology of orthotopic corneal transplants in mice. Invest Ophthalmol Vis Sci. 1999;40:2614–21.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Boisgérault F, Liu Y, Anosova N, Ehrlich E, Dana MR, Benichou G. Role of CD4+ and CD8+ T cells in allorecognition: lessons from corneal transplantation. J Immunol. 2001;167:1891–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Auchincloss H, Sultan H. Antigen processing and presentation in transplantation. CurrOpinImmunol. 1996;8:681–7.Google Scholar
  28. 28.
    Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52.  https://doi.org/10.1038/32588.CrossRefGoogle Scholar
  29. 29.
    Steinman RM. Dendritic cells and the control of immunity: enhancing the efficiency of antigen presentation. Mt Sinai J Med. 2001;68:160–6.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Amescua G, Collings F, Sidani A, Bonfield TL, Rodriguez JP, Galor A, Medina C, Yang X, Perez VL. Effect of CXCL-1/KC production in high risk vascularized corneal allografts on T cell recruitment and graft rejection. Transplantation. 2008;85:615–25.  https://doi.org/10.1097/TP.0b013e3181636d9d.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Vignali DAA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523–32.  https://doi.org/10.1038/nri2343.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Chauhan SK, Saban DR, Lee HK, Dana R. Levels of Foxp3 in regulatory T cells reflect their functional status in transplantation. J Immunol. 2009;182:148–53.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Tahvildari M, Omoto M, Chen Y, Emami-Naeini P, Inomata T, Dohlman TH, Kaye AE, Chauhan SK, Dana R.In vivo expansion of regulatory T cells by low-dose interleukin-2 treatment increases allograft survival in corneal transplantation. Transplantation 2016;100. doi: https://doi.org/10.1097/TP.0000000000001044.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Inomata T, Hua J, Di Zazzo A, Dana R. Impaired function of peripherally induced regulatory T cells in hosts at high risk of graft rejection. Sci Rep. 2016;6:39924.  https://doi.org/10.1038/srep39924.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ding Y, Xu J, Bromberg JS. Regulatory T cell migration during an immune response. Trends Immunol. 2012;33:174–80.  https://doi.org/10.1016/j.it.2012.01.002.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Chauhan SK, Saban DR, Dohlman TH, Dana R. CCL-21 conditioned regulatory T cells induce allotolerance through enhanced homing to lymphoid tissue. J Immunol. 2014;192:817–23.  https://doi.org/10.4049/jimmunol.1203469.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ueha S, Yoneyama H, Hontsu S, Kurachi M, Kitabatake M, Abe J, Yoshie O, Shibayama S, Sugiyama T, Matsushima K. CCR7 mediates the migration of Foxp3 + regulatory T cells to the paracortical areas of peripheral lymph nodes through high endothelial venules. J LeukocBiol. 2007;82:1230–8.  https://doi.org/10.1189/jlb.0906574.CrossRefGoogle Scholar
  38. 38.
    Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and differences. Immunol Rev. 2014;259:88–102.  https://doi.org/10.1111/imr.12160.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H, Fehling HJ, Bluestone JA. Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity. 2013;39:949–62.  https://doi.org/10.1016/j.immuni.2013.10.016.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2013;20:62–8.  https://doi.org/10.1038/nm.3432.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hua J, Inomata T, Chen Y, Foulsham W, Stevenson W, Shiang T, Bluestone JAJA, Dana R. Pathological conversion of regulatory T cells is associated with loss of allotolerance. Sci Rep. 2018;8:7059.  https://doi.org/10.1038/s41598-018-25384-x.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Lee YK, Mukasa R, Hatton RD, Weaver CT. Developmental plasticity of Th17 and Treg cells. CurrOpinImmunol. 2009;21:274–80.  https://doi.org/10.1016/J.COI.2009.05.021.CrossRefGoogle Scholar
  43. 43.
    Benghiat FS, Charbonnier LM, Vokaer B, De WV, Le MA. Interleukin 17–producing T helper cells in alloimmunity. Transplant Rev. 2009;23:11–8.  https://doi.org/10.1016/j.trre.2008.08.007.CrossRefGoogle Scholar
  44. 44.
    Heidt S, San D, Chadha R, Wood KJ, Wood KJ. The impact of Th17 cells on transplant rejection and the induction of tolerance. CurrOpin Organ Transplant. 2010;15:456–61.  https://doi.org/10.1097/MOT.0b013e32833b9bfb.CrossRefGoogle Scholar
  45. 45.
    Chen H, Wang W, Xie H, Xu X, Wu J, Jiang Z, Zhang M, Zhou L, Zheng S. A pathogenic role of IL- 17 at the early stage of corneal allograft rejection. TransplImmunol. 2009;21:155–61.  https://doi.org/10.1016/j.trim.2009.03.006.CrossRefGoogle Scholar
  46. 46.
    Cunnusamy K, Chen PW, Niederkorn JY. IL-17 promotes immune privilege of corneal allografts. J Immunol. 2010;185:4651–8.  https://doi.org/10.4049/jimmunol.1001576.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol. 2007;7:610–21.  https://doi.org/10.1038/nri2132.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Moreau A, Varey E, Bouchet-Delbos L, Cuturi M-C. Cell therapy using tolerogenic dendritic cells in transplantation. Transplant Res. 2012;1:13.  https://doi.org/10.1186/2047-1440-1-13.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Hattori T, Saban DR, Emami-naeini P, Chauhan SK, Funaki T, Ueno H, Dana R. Donor-derived, tolerogenic dendritic cells suppress immune rejection in the indirect allosensitization-dominant setting of corneal transplantation. J LeukocBiol. 2012;91:621–7.  https://doi.org/10.1189/jlb.1011500.CrossRefGoogle Scholar
  50. 50.
    Tahvildari M, Emami-Naeini P, Omoto M, Mashaghi A, Chauhan SK, Dana R. Treatment of donor corneal tissue with immunomodulatory cytokines: a novel strategy to promote graft survival in high-risk corneal transplantation. Sci Rep. 2017;7:971.  https://doi.org/10.1038/s41598-017-01065-z.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Albuquerque RJC, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A, Baffi JZ, Yamada K, Kaneko H, Green MG, Chappell J, Wilting J, Weich HA, Yamagami S, Amano S, Mizuki N, Alexander JS, Peterson ML, Brekken RA, et al. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med. 2009;15:1023–30.  https://doi.org/10.1038/nm.2018.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Cursiefen C, Chen L, Saint-Geniez M, Hamrah P, Jin Y, Rashid S, Pytowski B, Persaud K, Wu Y, Streilein JW, Dana R. Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. ProcNatlAcadSci. 2006;103:11405–10.  https://doi.org/10.1073/pnas.0506112103.CrossRefGoogle Scholar
  53. 53.
    Ambati BK, Nozaki M, Singh N, Takeda A, Jani PD, Suthar T, Albuquerque RJC, Richter E, Sakurai E, Newcomb MT, Kleinman ME, Caldwell RB, Lin Q, Ogura Y, Orecchia A, Samuelson DA, Agnew DW, St Leger J, Green WR, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature. 2006;443:993–7.  https://doi.org/10.1038/nature05249.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Tan Y, Cruz-Guilloty F, Medina-Mendez CA, Cutrufello NJ, Martinez RE, Urbieta M, Wilson D, Li Y, Perez VL. Immunological disruption of antiangiogenicsignals by recruited allospecific T cells leads to corneal allograft rejection. J Immunol. 2012;188:5962–9.  https://doi.org/10.4049/jimmunol.1103216.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Cursiefen C, Masli S, Ng TF, Dana MR, Bornstein P, Lawler J, Streilein JW. Roles of thrombospondin-1 and -2 in regulating corneal and iris angiogenesis. Invest Ophthalmol Vis Sci. 2004;45:1117–24.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Jin Y, Chauhan SK, El Annan J, Annan JEI, Sage PT, Sharpe AH, Dana R. A novel function for programmed death ligand-1regulation of angiogenesis. Am J Pathol. 2011;178:1922–9.  https://doi.org/10.1016/j.ajpath.2010.12.027.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Ferrari G, Hajrasouliha AR, Sadrai Z, Ueno H, Chauhan SK, Dana R. Nerves and neovessels inhibit each other in the cornea. Invest Ophthalmol Vis Sci. 2013;54:813–20.  https://doi.org/10.1167/iovs.11-8379.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Cursiefen C, Maruyama K, Bock F, Saban D, Sadrai Z, Lawler J, Dana R, Masli S. Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J Exp Med. 2011;208:1083–92.  https://doi.org/10.1084/jem.20092277.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Strasser A, Jost PJ, Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity. 2009;30:180–92.  https://doi.org/10.1016/j.immuni.2009.01.001.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Stuart PM, Griffith TS, Usui N, Pepose J, Yu X, Ferguson TA. CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. J Clin Invest. 1997;99:396–402.  https://doi.org/10.1172/JCI119173.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Yamagami S, Kawashima H, Tsuru T, Yamagami H, Kayagaki N, Yagita H, Okumura K, Gregerson DS. Role of Fas-Fas ligand interactions in the immunorejection of allogeneic mouse corneal transplants. Transplantation. 1997;64:1107–11.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Yang W, Li H, Chen PW, Alizadeh H, He Y, Hogan RN, Niederkorn JY. PD-L1 expression on human ocular cells and its possible role in regulating immune-mediated ocular inflammation. InvestigOpthalmol Vis Sci. 2009;50:273.  https://doi.org/10.1167/iovs.08-2397.CrossRefGoogle Scholar
  63. 63.
    Shen L, Jin Y, Freeman GJ, Sharpe AH, Dana MR. The function of donor versus recipient programmed death-ligand 1 in corneal allograft survival. J Immunol. 2007;179:3672–9.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Dana MR, Dai R, Zhu S, Yamada J, Streilein JW. Interleukin-1 receptor antagonist suppresses Langerhans cell activity and promotes ocular immune privilege. Invest Ophthalmol Vis Sci. 1998;39:70–7.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Dana MR, Yamada J, Streilein JW. Topical interleukin 1 receptor antagonist promotes corneal transplant survival. Transplantation. 1997;63:1501–7.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Contreras-Ruiz L, Masli S. Immunomodulatory cross-talk between conjunctival goblet cells and dendritic cells. PLoS One. 2015;10:e0120284.  https://doi.org/10.1371/journal.pone.0120284.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Saban DR, Bock F, Chauhan SK, Masli S, Dana R. Thrombospondin-1 derived from APCs regulates their capacity for allosensitization. J Immunol. 2010;185:4691–7.  https://doi.org/10.4049/jimmunol.1001133.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Hamrah P, Haskova Z, Taylor AW, Zhang Q, Ksander BR, Dana MR. Local treatment with alpha-melanocyte stimulating hormone reduces corneal allorejection. Transplantation. 2009;88:180–7.  https://doi.org/10.1097/TP.0b013e3181ac11ea.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Satitpitakul V, Sun Z, Suri K, Amouzegar A, Katikireddy KR, Jurkunas UV, Kheirkhah A, Dana R. Vasoactive intestinal peptide promotes corneal allograft survival. Am J Pathol. 2018;188:2016–24.  https://doi.org/10.1016/j.ajpath.2018.05.010.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Sabatino F, Di Zazzo A, De Simone L, Bonini S. The intriguing role of neuropeptides at the ocular surface. Ocul Surf. 2017;15:2–14.  https://doi.org/10.1016/j.jtos.2016.10.003.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Abud TB, Di Zazzo A, Kheirkhah A, Dana R. Systemic immunomodulatorystrategies in high-risk corneal transplantation. J Ophthalmic Vis Res. 2017;12:81–92.  https://doi.org/10.4103/2008-322X.200156.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Guo X, Jie Y, Ren D, Zeng H, Zhang Y, He Y, Pan Z. In vitro-expanded CD4(+)CD25(high)Foxp3(+) regulatory T cells controls corneal allograft rejection. Hum Immunol. 2012;73:1061–7.  https://doi.org/10.1016/j.humimm.2012.08.014.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Shao C, Chen Y, Nakao T, Amouzegar A, Yin J, Tahvildari M, Lužnik Z, Chauhan SK, Dana R. Local delivery of regulatory T cells promotes corneal allograft survival. Transplantation. 2018;103:182.  https://doi.org/10.1097/TP.0000000000002442.CrossRefGoogle Scholar
  74. 74.
    Omoto M, Katikireddy KR, Rezazadeh A, Dohlman TH, Chauhan SK. Mesenchymal stem cells home to inflamed ocular surface and suppress allosensitization in corneal transplantation. Invest Ophthalmol Vis Sci. 2014;55:6631–8.  https://doi.org/10.1167/iovs.14-15413.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Oh JY, Lee RH, Yu JM, Ko JH, Lee HJ, Ko AY, Roddy GW, Prockop DJ. Intravenous mesenchymal stem cells prevented rejection of allogeneic corneal transplants by aborting the early inflammatory response. MolTher. 2012;20:2143–52.  https://doi.org/10.1038/mt.2012.165.CrossRefGoogle Scholar
  76. 76.
    Xu Q, Tan X, Zhang Y, Jie Y, Pan Z. Subconjunctival injection of in vitro transforming growth factor-β-induced regulatory T cells prolongs allogeneic corneal graft survival in mice. Int J ClinExp Med. 2015;8:20271–8.Google Scholar
  77. 77.
    Emami-Naeini P, Dohlman TH, Omoto M, Hattori T, Chen Y, Lee HS, Chauhan SK, Dana R. Soluble vascular endothelial growth factor receptor-3 suppresses allosensitization and promotes corneal allograft survival. Graefes Arch ClinExpOphthalmol. 2014;252:1755–62.  https://doi.org/10.1007/s00417-014-2749-5.CrossRefGoogle Scholar
  78. 78.
    Dohlman TH, Omoto M, Hua J, Stevenson W, Lee S-M, Chauhan SK, Dana R. VEGF-trap afliberceptsignificantly improves long-term graft survival in high-risk corneal transplantation. Transplantation. 2015;99:678–86.  https://doi.org/10.1097/TP.0000000000000512.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Fasciani R, Mosca L, Giannico MI, Ambrogio SA, Balestrazzi E. Subconjunctival and/or intrastromalbevacizumab injections as preconditioning therapy to promote corneal graft survival. IntOphthalmol. 2015;35:221–7.  https://doi.org/10.1007/s10792-014-9938-4.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Victor L. Perez
    • 1
  • William Foulsham
    • 2
  • Kristen Peterson
    • 3
  • Reza Dana
    • 4
    Email author
  1. 1.Duke Eye CenterDepartment of OphthalmologyDurhamUSA
  2. 2.Schepens Eye Research Institute, Massachusetts Eye and Ear InfirmaryDepartment of Ophthalmology, Harvard Medical SchoolBostonUSA
  3. 3.Duke UniversityDepartment of OphthalmologyDurhamUSA
  4. 4.Harvard Medical SchoolCornea & Refractive Surgery, Massachusetts Eye & EarBostonUSA

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