Though keratoplasty is the most successful transplantation [1], corneal graft rejection is still the most frequent complication after corneal grafting and often leads to irreversible transplant failure. A recently published study on the outcome of corneal graft rejection showed that 49% of transplant rejections were irreversible [2]. The rate of reversibility was influenced by preoperative diagnosis and by corneal thickness at the time of first diagnosis of rejection. Patients who received a corneal graft because of bullous keratopathy or because of prior graft failure had a higher risk of graft rejection than patients with keratoconus or Fuchs’ endothelial dystrophy. Moreover, grafts that underwent irreversible rejection were significantly thicker at the time of rejection diagnosis than transplants that cleared up after the rejection episode. Another recent study focusing on regrafting confirmed the influence of repeated transplantation on graft survival [3]. While 37 and 43% of first and second regrafts survived the follow-up period, the percentage of clear grafts decreased to 25 and 0% for the third and fourth regrafts. Immune reactions occurred in 31% of all observed transplants (regrafts). These findings indicate that prevention and therapy of allograft rejection is still the most challenging field of today’s keratoplasty.

1.
Barron BA: Penetrating keratoplasty; in Kaufman HE, Barron BA, McDonald MB (eds): The Cornea, ed 2, Boston, Butterworth-Heinemann, 1998, pp 805–845.
2.
Naacke HG, Borderie VM, Bourcier T, Touzou O, Moldovan M, Laro M: Outcome of corneal transplantation rejection. Cornea 2001;20:350–353.
3.
Bersudsky V, Blum-Hareuveni T, Rehany U, Rumelt S: The profile of repeated corneal transplantation. Ophthalmology 2001;108:461–469.
4.
Whitsett CF, Stulting RD: The distribution of HLA antigens on human corneal tissue. Invest Ophthalmol Vis Sci 1984;25:519–524.
5.
Fujikawa LS, Colvin RB, Bann AK: Expression of HLA-A/B/C and DR locus antigens on epithelial, stromal and endothelial cells of the human cornea. Cornea 1982;1:213–218.
6.
Young E, Stark WJ, Predergast RA: Immunology of corneal allograft rejection: HLA-DR antigens on human corneal cells. Invest Ophthalmol Vis Sci 1985;26:571–576.
7.
Tressler PA, Foulks GN, Sanfilippo F: The expression of HLA antigens on human corneal tissue. Am J Ophthalmol 1984;98:763–772.
8.
Völcker-Dieben HJ, D’Amero J, Kruit PJ, De Lange P: Interaction between prognostic factors for corneal allograft survival. Transplant Proc 1989;21:3135–3138.
9.
Irschick E, Miller K, Berger M, et al: Studies of the mechanism of tolerance induced by short term immunosuppression with cyclosporin in high risk corneal allograft recipients. I. Analysis of CTL precursor frequencies. Transplantation 1989;48:986–990.
10.
Hahn AB, Foulks GN, Enger C, Fink N, Stark WJ, Hopkins KA, Sanfilippo F: The association of lymphocytotoxic antibodies with corneal allograft rejection in high-risk patients: The collaborative Corneal Transplantation Studies Research Group. Transplantation 1995;59:21–27.
11.
Roy R, Boisjoly HM, Wagner E, Langlois A, Bernard PM, Bazin R, Laughrea PA, Dube I: Pretransplant and posttransplant antibodies in human corneal transplantation. Transplantation 1992;54:463–467.
12.
Gibbs DC, Batchelor JR, Werb A, Schlesinger W, Casey TA: The influence of tissue-type compatibility on the fate of full-thickness corneal grafts. Trans Ophthalmol Soc UK 1974;94:101–126.
13.
Böhnke M, Vogelberg K: HLA-Antigene and Keratoplastik. Fortschr Ophthalmol 1987;84:519–528.
14.
Boisjoly HM, Roy R, Bernard PM, Dubé I, Laughrea PA, Bazin R: HLA-A, -B, -DR matching in corneal transplantation. Ophthalmology 1986;93:1290–1295.
15.
Foulks GN, Sanfilippo FP, Locascio JA, MacQueen JM, Dawson DV: Histocompatibility testing for keratoplasty in high-risk patients. Ophthalmology 1983;90:239–244.
16.
Hoffmann F, von Keyserlingk HJ, Wiederholt M: Die Bedeutung der HLA-Typisierung bei Hornhauttransplantaten mit ungünstiger Prognose unter Cyclosporintherapie. Fortschr Ophthalmol 1986;83:542–546.
17.
Sanfilippo FP, MacQueen JM, Vaughn WK, Foulks GN: Reduced graft rejection with good HLA-A and -B matching in high risk corneal transplantation. N Engl J Med 1986;315:29–35.
18.
Völcker-Dieben HJ, Kok-van Alphen CC, Landsberger Q, Persijn GG: Advances and disappointments, indications and restrictions regarding HLA-matched corneal grafts in high-risk cases. Doc Ophthalmol 1982;46:219–226.
19.
Boisjoly HM, Tourigny R, Bazin R, Laughrea PA, Dubé I, Chamberland G, Bernier J, Roy R: Risk factors of corneal graft failure. Ophthalmology 1993;100:1728–1735.
20.
Boisjoly HM, Roy R, Bernard PM, Dubé I, Laughrea PA, Bazin R: Association between corneal allograft reactions and HLA compatibility. Ophthalmology 1990;97:1689–1698.
21.
Boisjoly HM, Dubé I, Laughfrea PA, Roy R, Bernard PM: Rejection following corneal transplantation: Effects of HLA compatibility of the grafts. Clin Invest Med 1989;12:221–223.
22.
Hirsch N, Nolle B, Zavazava N, Westphal E, Duncker G, Rochels R, Muller-Ruchholtz W: HLA typing in high-risk keratoplasty. Ophthalmologe 1993;90:174–177.
23.
Bradley BA, Vail A, Gore SM, Rogers CA, Armitage WJ, Nicholls SM, Easty DL: Penetrating keratoplasty in the United Kingdom: An interim analysis of the corneal transplant follow-up study. Clin Transpl 1993:293–315.
24.
Ozdemir O: A prospective study of histocompatibility testing for keratoplasty in high-risk patients. Br J Ophthalmol 1986;70:183–186.
25.
Batchelor JR, Casey TA, Gibbs DC: HLA matching and corneal grafting. Lancet 1976;i:551–554.
26.
Beekhuis WH, van Rij G, Renardel de Lavalette JGC, Rinkel-van Driel E, Persijn G, d’Amero J: Corneal graft survival in HLA-A and HLA-B matched transplantations in high-risk cases with retrospective review of HLA-DR compatibility. Cornea 1991;10:9–12.
27.
Baumgartner I, Mayr WR, Hajek-Rosenmayr A, Grabner G: Differential effect of incompatibilities of the HLA-A and HLA-B locus on the success of corneal transplants. Klin Monatsbl Augenheilkd 1988;193:48–51.
28.
Hoffmann Fregel M, Noske W, Bunte S: HLA-B and -DR match reduces the allograft reaction after keratoplasty. Ger J Ophthalmol 1994;3:100–104.
29.
Völcker-Dieben H, Claas FHJ, Schreuder GMT, Schipper RF, Pels E, Persjin GG, Smits J, D’Amero J: Beneficial effects of HLA-DR matching on the survival of corneal allografts. Transplantation 2000;70:640–648.
30.
Baggesen K, Ehlers N, Lamm LU: HLA-DR/RFLP compatible corneal grafts. Acta Ophthalmol 1991;69:229–233.
31.
Gore SM, Vail A, Bradley BA, Rogers CA, Easty DL, Armitage WJ: HLA-DR matching in corneal transplantation. Transplantation 1995;60:1033–1039.
32.
Bradley BA, Vail A, Gore SM: Negative effects of HLA-DR matching on corneal transplant rejection. Transplant Proc 1994;27:1392–1398.
33.
Vail A, Gore SM, Bradley BA, Easty DL, Rogers CA, Armitage WJ: Influence of donor and histocompatibility factors on corneal graft outcome. Transplantation 1994;58:1210–1216.
34.
The Collaborative Corneal Transplantation Studies Research Group CCTS: Effectiveness of histocompatibility matching in high risk corneal transplantation. Arch Ophthalmol 1992;110:1392–1403.
35.
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. Hum Immunol 1992;33:132–141.
36.
Klein J: Natural History of the Major Histocompatibility Complex. New York, Wiley & Sons, 1987.
37.
He YG, Mellon J, Niederkorn JK: The effect of oral immunization on corneal allograft survival. Transplantation 1996;61:920–926.
38.
Pleyer U, Milani JH, Dukes A, Chou J, Mondino BJ: Effects of liposome encapsulated anti CD4 monoclonal antibodies on orthotopic corneal allografts in a rat model. Invest Ophthalmol Vis Sci 1995;35:52–61.
39.
Nicholls SM, Bradley BB, Easty DL: Effect of mismatches for major histocompatibility complex and minor antigens on corneal graft rejection. Invest Ophthalmol Vis Sci 1991;32:2729–2734.
40.
Buxton JN, Apisson JG, Hoeffle FB: Corticosteroids in 100 keratoplasties. Am J Ophthalmol 1969;67:46–51.
41.
Beato M: Gene regulation by steroid hormones. Cell 1989;56:335–344.
42.
Harrison RN, Lippman SS: How steroid hormones work. Hosp Pract 1989;24:63–76.
43.
Leibovitz HM, Kupfermann A: Kinetics of topically administered prednisolone acetate. Arch Ophthalmol 1976;94:1387–1389.
44.
Leibovitz HM: Management of inflammation in the cornea and conjunctiva. Ophthalmology 1980;87:753–757.
45.
Coster DJ: Mechanisms of corneal graft failure: The erosion of corneal privilege. Eye 1989;2:252–262.
46.
Rinne JR, Stulting RD: Current practice in the prevention and treatment of corneal allograft rejection. Cornea 1992;11:326–328.
47.
Sugar A, Bokosky JE, Meyer RF: A randomized trial of topical corticosteroids in epithelial healing after keratoplasty. Cornea 1993;3:268–271.
48.
Donish PC, Cavanagh D, Borichoff SA, Dohlman CH: Posterior subcapsular cataract induced by topical corticosteroids following keratoplasty for keratoconus. Ann Opthalmol 1981;13:12–15.
49.
Sigal NH, Dumont FJ: Cyclosporin A, FK506 and rapamycin: Pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol 1992;10:519–560.
50.
Takahashi N, Hayano T, Suzuki M: Peptidyl-propyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin. Nature 1989;337:473.
51.
Pleyer U, Raphael B, Kosmidis P, Ryffel B, Thiel HJ: Verteilung von Cyclophilin in okulären Geweben. Ophthalmologe 1993;90:118.
52.
Borel JF: Pharmacology of cyclosporine (Sandimmun). Pharmacol Rev 1989;41:239–242.
53.
Nussenblatt RB, Palestine AG: Cyclosporine: Immunology, pharmacology and therapeutic uses. Surv Ophthalmol 1986;31:159–169.
54.
Hess AD, Esa AH, Colombani PM: Mechanism of action of cyclosporine: Effects on cells of the immune system and on subcellular events in T-cell activation. Transplant Proc 1988;20:29–40.
55.
Belin MW, Bouchard CS, Frantz S, Chielinska J: Topical cyclosprine in high risk corneal transplants. Ophthalmology 1989;96:1144–1150.
56.
Milani J, Pleyer U, Dukes A, Chou HJ, Lutz S, Rückert D, Schmidt KH, Mondino BJ: Prolongation of corneal allograft survival with liposome-encapsulated cyclosporine in the rat eye. Ophthalmology 1993;100:890–896.
57.
DeRojas Silva MV, Rodriguez-Ares MT, Sanchez-Salorio M, Lamas DMJ, Cuevas Alvarez J, Vila Jato JL, Capeans Tome C: Efficacy of subconjunctival cyclosporine-containing microspheres on keratoplasty rejection in the rabbit. Graefe’s Arch Clin Exp Ophthalmol 1999;237:840–847.
58.
Inoue K, Amano S, Kimura C, Sato T, Fujita N, Kagaya F, Kaji Y, Oshika T, Araie M: Long-term effects of topical cyclosporine A treatment after penetrating keratoplasty. Jpn J Ophthalmol 2000;44:302–305.
59.
Perry HD, Donnenfeld ED, Acheampong A, Kanellopoulos AJ, Sforza d’Aversa G, Wallerstein A, Stern M: Topical cyclosporine A in the management of postkeratoplasty glaucoma and corticosteroid-induced ocular hypertension and the penetration of topical 0.5% cyclosporine A into the cornea and anterior chamber. Ophthalmology 1998;105:1550–1556.
60.
Pleyer U, Weidle EG, Thiel HJ: The use of cyclosporine in high-risk keratoplasty. Am J Ophthalmol 1989;108:467–468.
61.
Sundmacher R, Reinhard T, Heering P: Six years experience with systemic cyclosporin A prophylaxis in high risk perforating keratoplasty patients. Ger J Ophthalmol 1992;1:432–436.
62.
Sundmacher R, Reinhard T: Cyclosporin A in high risk perforating keratoplasty; in Zierhut M, Pleyer U, Thiel HJ (eds): Immunology of corneal transplantation. Amsterdam, Aeolus, 1994, pp 233–238.
63.
Hill JC: The use of cyclosporine in high-risk keratoplasty. Am J Ophthalmol 1989;107:506–510.
64.
Miller K, Huber C, Niederwieser D, Göttinger W: Successful engraftment of high-risk corneal allografts with short-term immuno-suppression with cyclosporine. Transplantation 1988;45:651–653.
65.
Hill JC: Systemic cyclosporine in high-risk keratoplasty. Ophthalmology 1994;101:128–133.
66.
Robert PY, Delbose B, Preux PM, Monnot PH, Drouet M, Peyronet P, Adenis JP: Treatment with cyclosporine A, with low doses, in high-risk penetrating keratoplasties: A bicentric study of 90 cases. J Fr Ophthalmol 1997;20:507–514.
67.
Barker NH, Henderson RPM, Ross CA, Coster DJ, Williams KA: Current Australian practice in the prevention and management of corneal allograft rejection. Clin Exp Ophthalmol 2000;28:357–360.
68.
Sollinger HW, Belzer FO, Deierhoi MH, et al. RS-61443 (mycophenolate mofetil): A multicenter study for refractory kidney transplant rejection. Ann Surg 1992;216:513–519.
69.
Ensley RD, Bristow MR, Olsen SL, et al: The use of mycophenolate mofetil (RS-61443) in human heart transplant recipients. Transplantation 1993;56:78–82.
70.
Goldblum R: Therapy of rheumatoid arthritis with mycophenolate mofetil. Clin Exp Rheumatol 1993;11(suppl 8):117–119.
71.
Bohm M, Beissert S, Schwarz T, Metze D, Luger T: Bullous pemphigoid treated with mycophenolate mofetil. Lancet 1997;349:541.
72.
Reis A, Reinhard T, Voiculescu A, et al: Mycophenolate mofetil versus cyclosporine A in high-risk keratoplasty patients: A prospectively randomised clinical trial. Br J Ophthalmol 1999;83:1268–1273.
73.
Reis A, Megahed M, Reinhard T, Godehardt E, Spelsberg H, Braunstein C, Sundmacher R: Coadministration of the new macrolide immunosuppressant RAD and mycophenolate mofetil in experimental corneal transplantation. Transplantation 2000;70:1397–1407.
74.
Morris RE, Shorthouse R: A study of the contrasting effects of cyclosporine FK506 and rapamycin on suppression of allograft rejection. Transplant Proc 1990;22:1638–1641.
75.
Pleyer U, Lutz S, Jusko WJ, Nguyen K, Narawane M, Rückert D, Mondino BJ, Lee VHL: Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye. Invest Ophthalmol Vis Sci 1993;34:2737–2742.
76.
Nishi M, Herbort CP, Matsubara M, Morishita Y, Nishimura M, Nieda M, Mori S, Mochizuki M: Effects of the immunosuppressant FK506 on a penetrating keratoplasty rejection model in the rat. Invest Ophthalmol Vis Sci 1993;34:2477–2486.
77.
Mills RA, Jones DB, Winkler CR, Wallace GW, Wilhelmus KR: Topical FK506 prevents experimental corneal allograft rejection. Cornea 1995;14:157–160.
78.
Tchah H, Lim B: Effect of FK506 on the cornea: Use of topical FK506 in corneal transplantation in a guinea pig-rat model. Korean J Ophthalmol 1999;13:71–77.
79.
Shapiro R, Fung JJ, Jain A, Parks P, Todo S, Starzl TE: The side effects of FK506 in humans. Transplant Proc 1990;22:41–43.
80.
Holbach LM, Hinzpeter EN, Naumann GOH: Keratoplastik; in Naumann GOH (ed): Pathologie des Auges. Berlin, Springer, 1997, pp 642–650.
81.
Mush DC, Schwartz AE, Fithgerald-Shelton K, Sugar A, Meyer RF: The effect of allograft rejection after penetrating keratoplasty on central endothelial cell density. Am J Ophthalmol 1991;111:739–742.
82.
Hudde T, Minassian DC, Larkin DFP: Randomised controlled trial of corticosteroid regimens in endothelial corneal allograft rejection. Br J Ophthalmol 1999;83:1348–1352.
83.
Lam DS, Wong AK, Tham CC, Leung AT: The use of combined intravenous pulse methylprednisolone and oral cyclosporine A in the treatment of corneal graft rejection: A preliminary study. Eye 1998;12:615–618.
84.
Thiel MA, Ross CA, Coster DJ: Corneal allograft rejection: Has the time come for intravenous pulsed methylprednisolone? A debate. Clin Exp Ophthalmol 2000;28:398–404.
85.
Yamagami S, Dana MR: The critical role of lympho nodes in corneal alloimmunization and graft rejection. Invest Ophthalmol Vis Sci 2001;42:1293–1298.
86.
Thompson JF, Chalmers DH, Wood RF, Kirkham SR, Morris PJ: Sudden death following high-dose intravenous methyl-prednisolone. Transplantation 1983;36:594–596.
87.
Pleyer U, Dannowski H, Volk HD, Ritter T: Corneal allograft rejection: Current understanding. I. Immunology and basic mechanisms. Ophthalmologica 2001;215:254–262.
88.
Ippoliti G, Fronterre A: Usefulness of CD3 or CD6 anti-T monoclonal antibodies in the treatment of acute corneal graft rejection. Transplant Proc 1989;21:3133–3134.
89.
Newman DK, Isaacs JD, Watson PG, Meyer PA, Hale G, Waldmann H: Prevention of immune-mediated corneal graft destruction with the anti-lymphocyte monoclonal antibody, CAMPATH-1H. Eye 1995;9:564–569.
90.
Masuda I, Matsuo T, Yasuda T, Matsuo N: Gene transfer with liposomes to the intraocular tissues by different routes of administration. Invest Ophthalmol Vis Sci 1996;37:1914–1920.
91.
Larkin DFP, Oral HB, Ring CJA, Lemoine NR, George AJT: Adenovirus-mediated gene delivery to the corneal endothelium. Transplantation 1996;61:363–370.
92.
Pleyer U, Bertelmann E, Volk HD, Hartmann C, Ritter T: Gene transfer of (viral) interleukin-10 but not interleukin-4 prolongs allograft survival in experimental keratoplasty: Invest Ophthalmol Vis Sci 2000;41(suppl):543.
93.
Munkhbat B, Hagihara M, Shimazaki J, Kanai N, Morita N, Gansuvd B, Kato S, Tsubota K, Tsuji K: The impact of HLA-A matching in corneal transplantation. Tokai J Exp Clin Med 1999;24:63–71.
94.
Hill JC, Creemers PC: An adverse matching effect for the HLA-B locus in corneal transplantation. Transpl Int 1997;10:145–149.
95.
Fink N, Stark WJ, Maguire MG, Stulting D, Meyer R, Foulks G, Smith RE, Rapoza P: Effectiveness of histocompatibility matching in high-risk corneal transplantation: a summary of results from the collaborative corneal transplantation studies. Cesk Oftalmol 1994;50:3–12.
96.
Reinhard T, Moller M, Sundmacher R: Penetrating keratoplasty in patients with atopic dermatitis with and without systemic cyclosporin A. Cornea 1999;18:645–651.
97.
Reinhard T, Sundmacher R, Godehard E, Heering P: Preventive systemic cyclosporin A after keratoplasty at increased risk for immune reactions as the only elevated risk factor. Ophthalmologe 1997;94:496–500.
© 2002 S. Karger AG, Basel
2002
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.