Skip to main content

Advertisement

SpringerLink
Log in

Graft failure IV. Immunologic mechanisms of corneal transplant rejection

  • Original paper
  • Published:
International Ophthalmology Aims and scope Submit manuscript

Abstract

Corneal transplantation is the oldest and the most common form of solid tissue transplantation in humans. Immunologic graft rejection is one of the main causes of short and long-term graft failure. Rejection involves donor tissue recognition and destruction by allo-specific immune cells of the recipient. This review outlines (1) the immunobiology of transplantation, with reference to ocular immune privilege, (2) factors that confer “high-risk” status to a graft and (3) the pathophysiologic mechanisms of corneal transplant rejection.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ACAID:

Anterior chamber-associated immune deviation

APCs:

Antigen presenting cells

α-MSH:

Alpha-melanocyte stimulating hormone

CALT:

Conjunctival associated lymphoid tissue

CCTS:

Collaborative corneal transplantation studies

CD:

Cluster differentiation

CGRP:

Calcitonin-gene related peptide

CRP:

Complement regulatory proteins

CTLA 4 Ig:

Cytotoxic T-lymphocyte-associated antigen 4 to human immunoglobulin

DAF:

Decay accelerating factor

DCs:

Dendritic cells

DTH:

Delayed type hypersensitivity

FasL:

Fas ligand

HLA:

Human leukocyte antigen

ICAM:

Intercellular adhesion molecule

IDO:

Indoleamine dioxygenase

iNOS:

Inducible nitric oxide synthase

Ig:

Immunoglobulin

IL-10:

Interleukin 10

IFN:

Interferon

LCs:

Langerhans cells

LYVE-1:

Lymphatic endothelium-specific hyaluronan receptor

MHC:

Major histocompatibility complex

MIF:

Macrophage inhibitory factor

MIP:

Macrophage inflammatory protein

NKT:

Natural Killer T cells

PD-L:

Programmed death ligand

RANTES:

Regulated on activation normal T cell expressed and secreted

SOM:

Somatostatin

TCR:

T cell receptors

TGF-β:

Transforming growth factor-β

TNF:

Tumor necrosis factor

VEGF:

Vascular endothelial growth factor

VIP:

Vasoactive intestinal peptide

References

  1. Zirm EK (1906) Eine erfolgreiche totale keratoplastik. Arch Fr Ophthalmol 64:580–593

    Article  Google Scholar 

  2. Frequently asked questions (2006) Available at: http://www.restorsight.org/general/faqs.html. Accessed 20 June 2006

  3. Coster DJ, Williams KA (2005) The impact of corneal allograft rejection on the long-term outcome of corneal transplantation. Am J Ophthalmol 140:1112–1122

    Article  PubMed  Google Scholar 

  4. Price FW Jr, Whitson WE, Collins KS, Marks RG (1993) Five-year corneal graft survival. A large, single-center patient cohort. Arch Ophthalmol 111:799–805

    PubMed  Google Scholar 

  5. Port FK, Dykstra DM, Merion RM, Wolfe RA (2005) Trends and results for organ donation and transplantation in the United States, 2004. Am J Transplant 5:843–849

    Article  PubMed  Google Scholar 

  6. Kuchle M, Cursiefen C, Nguyen NX et al (2002) Risk factors for corneal allograft rejection: intermediate results of a prospective normal-risk keratoplasty study. Graefes Arch Clin Exp Ophthalmol 240:580–584

    Article  PubMed  Google Scholar 

  7. Streilein JW, Yamada J, Dana MR, Ksander BR (1999) Anterior chamber-associated immune deviation, ocular immune privilege, and orthotopic corneal allografts. Transplant Proc 31:1472–1475

    Article  PubMed  CAS  Google Scholar 

  8. Thompson RW, Price MO, Bowers PJ, Price FW (2003) Long-term graft survival after penetrating keratoplasty. Ophthalmology 110:1396–1402

    Article  PubMed  Google Scholar 

  9. Ing JJ, Ing HH, Nelson LR et al (1998) Ten-year postoperative results of penetrating keratoplasty. Ophthalmology 105:1855–1865

    Article  PubMed  CAS  Google Scholar 

  10. Inoue K, Amano S, Oshika T et al (2000) A 10-year review of penetrating keratoplasty. Jpn J Ophthalmol 44:139–145

    Article  PubMed  CAS  Google Scholar 

  11. Williams KA, Muehlberg SM, Bartlett CM et al. (2000) The Australian Corneal graft Registry:1999 Report. Adelaide, Snap Printing

  12. MHC consortium (1999) Complete sequence and gene map of a human major histo-compatability complex. The MHC sequencing consortium. Nature 401:921–923

    Google Scholar 

  13. Khodadoust AA, Silverstein AM (1969) Transplantation and rejection of individual cell layers of the cornea. Invest Ophthalmol 8:180–195

    PubMed  CAS  Google Scholar 

  14. Khodadoust AA, Silverstein AM (1972) Studies on the nature of the privilege enjoyed by corneal allografts. Invest Ophthalmol 11:137–148

    PubMed  CAS  Google Scholar 

  15. Niederkorn JY (2001) Mechanisms of corneal graft rejection: the sixth annual Thygeson Lecture. Presented at the Ocular Microbiology and Immunology Group Meeting, October 21,2000. Cornea 20:675–679

    Article  PubMed  CAS  Google Scholar 

  16. Osawa H, Streilein JW (2005) MHC class I and II antigens as targets of rejection in penetrating keratoplasty in low- and high-risk mouse eyes. Cornea 24:312–318

    Article  PubMed  Google Scholar 

  17. 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 110:1392–1403

    Google Scholar 

  18. Boisjoly HM, Roy R, Bernard PM et al (1990) Association between corneal allograft reactions and HLA compatibility. Ophthalmology 97:1689–1698

    PubMed  CAS  Google Scholar 

  19. Sanfilippo F, MacQueen JM, Vaughn WK, Foulks GN (1986) Reduced graft rejection with good HLA-A and B matching in high-risk corneal transplantation. N Engl J Med 315:29–35

    Article  PubMed  CAS  Google Scholar 

  20. Bartels MC, Doxiadis II, Colen TP, Beekhuis WH (2003) Long-term outcome in high-risk corneal transplantation and the influence of HLA-A and HLA-B matching. Cornea 22:552–526

    Article  PubMed  Google Scholar 

  21. van Dooremaal IC (1873) Die Entwicklun der in fremden Grund versetzten lebenden Geweba. Graefes Arch Ophthalmol 19:358–373

    Google Scholar 

  22. Medawar PB (1948) Immunity to homologous grafted skin. III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 29:58–69

    CAS  PubMed  Google Scholar 

  23. Streilein JW (2003) Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 3:879–889

    Article  PubMed  CAS  Google Scholar 

  24. Streilein JW, Masli S, Takeuchi T, Kezuka T (2002) The eye’s view of antigen presentation. Hum Immunol 63:435–443

    Article  PubMed  CAS  Google Scholar 

  25. Niederkorn JY (2003) The immune privilege of corneal grafts. J Leukoc Biol 74:167–171

    Article  PubMed  CAS  Google Scholar 

  26. Williams KA, Coster DJ (1985) Penetrating corneal transplantation in the inbred rat: a new model. Invest Ophthalmol Vis Sci 26:23–30

    PubMed  CAS  Google Scholar 

  27. Niederkorn JY (2006) See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat Immunol 7:354–359

    Article  PubMed  CAS  Google Scholar 

  28. Streilein JW (2003) New thoughts in the immunology of corneal transplantation. Eye 17:943–948

    Article  PubMed  CAS  Google Scholar 

  29. Hori J, Streilein JW (2001) Role of recipient epithelium in promoting survival of orthotopic corneal allografts in mice. Invest Ophthalmol Vis Sci 42:720–726

    PubMed  CAS  Google Scholar 

  30. Cursiefen C, Chen L, Saint-Geniez M et al (2006) Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proc Natl Acad Sci USA 103:11405–11410

    Article  PubMed  CAS  Google Scholar 

  31. Dana MR, Streilein JW (1996) Loss and restoration of immune privilege in eyes with corneal neovascularization. Invest Ophthalmol Vis Sci 37:2485–2494

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  33. Zhivov A, Stave J, Vollmar B, Guthoff R (2005) In vivo confocal microscopic evaluation of Langerhans cell density and distribution in the normal human corneal epithelium. Graefes Arch Clin Exp Ophthalmol 243:1056–1061

    Article  PubMed  Google Scholar 

  34. Hamrah P, Zhang O, Liu Y, Dana MR (2002) Novel characterization of MHC class II-negative population of resident corneal Langerhans cell-type dendritic cells. Invest Ophthalmol Vis Sci 43:639–646

    PubMed  Google Scholar 

  35. Hori J, Wang M, Miyashita M, Tanemoto K, Takahashi H, Takemori T, Okumura K, Yagita H, Azuma M (2006) B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts. J Immunol 177:5928–5935

    PubMed  CAS  Google Scholar 

  36. Huq S, Liu Y, Benichou G, Dana MR (2004) Relevance of the direct pathway of sensitization in corneal transplantation is dictated by graft bed microenvironment. J Immunol 173:4464–4469

    PubMed  CAS  Google Scholar 

  37. Simon M, Fellner P, El-Shabrawi Y, Ardjomand N (2004) Influence of donor storage time on corneal allograft survival. Ophthalmology 11:1534–1538

    Article  Google Scholar 

  38. He YG, Niederkorn JY (1996) Depletion of donor-derived Langerhans cells promotes corneal allograft survival. Cornea 15:82–89

    Article  PubMed  CAS  Google Scholar 

  39. Hamrah P, Liu Y, Zhang Q, Dana MR (2003) The corneal stroma is endowed with a significant number of resident dendritic cells. Invest Ophthalmol Vis Sci 44:581–589

    Article  PubMed  Google Scholar 

  40. Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258

    Article  PubMed  CAS  Google Scholar 

  41. Hamrah P, Liu Y, Zhang Q, Dana MR (2003) Alterations in corneal stromal dendritic cell phenotype and distribution in inflammation. Arch Ophthalmol 121:1132–1140, Erratum in: Arch Ophthalmol 121:1555

    Article  PubMed  Google Scholar 

  42. Gong N, Pleyer U, Yang J, Vogt K et al (2006) Influence of local and systemic CTLA2Ig gene transfer on corneal allograft survival. J Gene Med 8:456–467

    Article  CAS  Google Scholar 

  43. Yamagami S, Miyazaki D, Ono SF, Dana MR (1999) Differential chemokine gene expression in corneal transplant rejection. Invest Ophthalmol Vis Sci 40:2892–2897

    PubMed  CAS  Google Scholar 

  44. Jin Y, Shen L, Chen L et al (2005) Expression of CCR7 by corneal antigen-presenting cells in inflammation. ARVO Abstr 2810/B363

  45. Cursiefen C, Cao J, Chen L et al (2004) Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. Invest Ophthalmol Vis Sci 45:2666–2673

    Article  PubMed  Google Scholar 

  46. Cursiefen C, Maruyama K, Jackson DG et al (2006) Time course of angiogenesis and lymphangiogenesis after brief corneal inflammation. Cornea 25:443–447

    Article  PubMed  Google Scholar 

  47. Cursiefen C, Chen L, Dana MR, Streilein JW (2003) Corneal lymphangiogenesis: evidence, mechanisms, and implications for corneal transplant immunology. Cornea 22:273–281

    Article  PubMed  Google Scholar 

  48. Allansmith MR, McClellan BH (1975) Immunoglobulins in the human cornea. Am J Ophthalmol 80:123–132

    PubMed  CAS  Google Scholar 

  49. Mondino BJ, Brady KJ (1981) Distribution of hemolytic complement in the normal cornea. Arch Ophthalmol 99:1430–1434

    PubMed  CAS  Google Scholar 

  50. Yamagami S, Dana MR (2001) The critical role of lymph nodes in corneal alloimmunization and graft rejection. Invest Ophthalmol Vis Sci 42:1293–1298

    PubMed  CAS  Google Scholar 

  51. Yamagami S, Dana MR, Tsuru T (2002) Draining lymph nodes play an essential role in alloimmunity generated in response to high-risk cornea transplantation. Cornea 21:405–409

    Article  PubMed  Google Scholar 

  52. Niederkorn JY, Wang S (2005) Immune privilege of the eye and fetus: parallel universes?. Transplantation 80:1139–1144

    Article  PubMed  Google Scholar 

  53. Chen L, Hamrah P, Cursiefen C et al (2004) Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Nat Med 10:813–815

    Article  PubMed  CAS  Google Scholar 

  54. Streilein JW, Masli S, Takeuchi M, Kezuka T (2002) The eye’s view of antigen presentation. Hum Immunol 63:435–443

    Article  PubMed  CAS  Google Scholar 

  55. Dana MR, Foster CS (2007) Regulation of immune response. In: Albert DM, Miller JW, Azar DT & Blodi BA (eds) Albert & Jakobiec’s principles and practice of ophthalmology, 3rd edn., section 2, chapter 10, Saunders Dec. 2007

  56. Streilein JW, Niederkorn JY (1981) Induction of anterior chamber-associated immune deviation requires an intact, functional spleen. J Exp Med 153:1058–1067

    Article  PubMed  CAS  Google Scholar 

  57. Neiderkorn JY, Mellon J (1996) Anterior-chamber associated immune deviation promotes corneal allograft survival. Invest Ophthalmol Vis Sci 37:2700–2707

    Google Scholar 

  58. Niederkorn JY (2006) See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat Immunol 7:354–359

    Article  PubMed  CAS  Google Scholar 

  59. Niederkorn JY (2002) Immune Privilege in the anterior chamber of the eye. Crit Rev Immunol 22:13–46

    PubMed  CAS  Google Scholar 

  60. Cardell SL (2006) The natural killer T lymphocyte: a player in the complex regulation of autoimmune diabetes in nonobese diabetic mice. Clin Exp Immunol 143:194–202

    Article  PubMed  CAS  Google Scholar 

  61. Hargrave SL, Mayhew E, Hegde S, Niederkorn J (2003) Are corneal cells susceptible to antibody-mediated killing in corneal allograft rejection?. Transplant Immunol 11:79–89

    Article  CAS  Google Scholar 

  62. Hegde S, Beauregard C, Mayhew E, Niederkorn JY (2005) CD4 (+) T-cell-mediated mechanisms of corneal allograft rejection: role of Fas-induced apoptosis. Transplantation 79:23–31

    Article  PubMed  CAS  Google Scholar 

  63. Niederkorn JY, Stevens C, Mellon J, Mayhew E (2006) Differential roles of CD 8 and CD 8− T lymphocytes in corneal allograft rejection in ‘high-risk’ hosts. Am J Transplant 6:705–713

    Article  PubMed  CAS  Google Scholar 

  64. Stuart PM, Griffith TS, Usui N et al (1997) CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. J Clin Invest 99:396–402

    Article  PubMed  CAS  Google Scholar 

  65. Stuart PM, Pan F, Plambeck S, Ferguson TA (2003) FasL–Fas interactions regulate neovascularization in the cornea. Invest Ophthalmol Vis Sci 44:93–98

    Article  PubMed  Google Scholar 

  66. Yamagami S, Kawashima H, Tsuru T et al (1997) Role of Fas-Fas ligand interactions in the immunorejection of allogeneic mouse corneal transplants. Transplantation 64:1107–1111

    Article  PubMed  CAS  Google Scholar 

  67. Stuart PM, Pan F, Yin X et al (2004) Effect of metalloprotease inhibitors on corneal allograft survival. Invest Ophthalmol Vis Sci 45:1169–1173

    Article  PubMed  Google Scholar 

  68. Jeng BH, Meisler DM, Hollyfield JG et al (2002) Nitric oxide generated by corneas in corneal storage media. Cornea 21:410–414

    Article  PubMed  Google Scholar 

  69. Sagoo P, Chan G, Larkin DF, George AJ (2004) Inflammatory cytokines induce apoptosis of corneal endothelium through nitric oxide. Invest Ophthalmol Vis Sci 45:3964–3973

    Article  PubMed  Google Scholar 

  70. Strestikova M, Plskova J, Filipec M, Farghali H (2003) FK 506 and aminoguanidine suppress iNOS induction in orthotopic corneal allografts and prolong graft survival in mice. Nitric Oxide 9:111–117

    Article  PubMed  CAS  Google Scholar 

  71. Beauregard C, Huq SO, Barabino S et al (2006) Keratocyte apoptosis and failure of corneal allografts. Transplantation 81:1–6

    Article  Google Scholar 

  72. Qian Y, Dekaris J, Yamagami S, Dana MR (2000) Topical soluble tumor necrosis factor receptor type I suppresses ocular chemokine gene expression and rejection of allogeneic corneal transplants. Arch Ophthalmol 118:1666–1671

    PubMed  CAS  Google Scholar 

  73. Yamada J, Dana MR, Zhu SN et al (1998) Interleukin 1 receptor antagonist suppresses allosensitization in corneal transplantation. Arch Ophthalmol 116:1351–1357

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work is supported by a grant (RO1-12963) from the National Institutes of Health, awarded to Dr Dana.

Author information

Authors and Affiliations

  1. Cornea Service, Massachusetts Eye and Ear Infirmary and Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Boston, MA, 02114, USA

    Eva-Marie Chong & M. Reza Dana

Authors
  1. Eva-Marie Chong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Reza Dana
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Reza Dana.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chong, EM., Dana, M.R. Graft failure IV. Immunologic mechanisms of corneal transplant rejection. Int Ophthalmol 28, 209–222 (2008). https://doi.org/10.1007/s10792-007-9099-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10792-007-9099-9

Keywords

Search

Navigation