Corneal Graft Rejection

Back

Background

Although described for more than 100 years, corneal transplantation has become increasingly common since the 1960s. In 2016, approximately 83,000 corneal transplantations were performed in the United States.[1] Corneal graft rejection is the most common cause of graft failure in the late postoperative period.[2]

Examples of corneal graft rejection are shown in the images below.



View Image

This severely vascularized cornea would be at high risk for graft rejection following a penetrating keratoplasty. This patient experienced Stevens-Joh....



View Image

This is an example of an acute graft rejection episode. Note the graft edema, Descemet folds, and keratic precipitates.

Pathophysiology

Corneal transplantation has a high success rate in part because of the relative immune privilege of the cornea. The cornea is avascular, limiting access of lymphocytes and other immune responsive cells.[3] There are no associated lymph nodes; therefore, the opportunity for presentation of foreign antigen to antigen-presenting cells and T cells is also limited. The cornea expresses MHC antigens to a lesser extent than other tissues, contributing to immune privilege. However, this can be compromised by prolonged inflammation, extensive vascularization, and other factors, resulting in rejection.

The term graft rejection refers to the specific immunologic response of the host to the donor corneal tissue. Because it is a specific process, it should be distinguished from other causes of graft failure that are not immune mediated. A corneal graft that has suffered this immunologic response may or may not ultimately fail. Some physicians distinguish between graft reaction, which is reversible with medical therapy, and graft rejection, in which the immunologic end stage has been reached and the process is irreversible. Other physicians simply use graft rejection to refer to this immunologic process at any stage of its development, noting that some cases progress to graft failure because of rejection. This second terminology is used in this article because it is in line with terminology used in other types of organ transplantation.

Furthermore, at the time of presentation, determining with certainty whether an immune process is reversible is impossible.

Ritter et al discuss the need for further study of the genetic modification of corneal grafts prior to surgery to prevent rejection.[4]

Epidemiology

Frequency

United States

In 2016, 82,994 corneal transplantations were performed in the United States.[1] The incidence of graft rejection varies widely depending on the study design, type of transplantation, and risk factors for rejection. Reported incidences of penetrating keratoplasty graft rejection range from 2.3% to 68%.[5] At 5 years’ follow-up in the Cornea Donor Study, 23% of subjects had at least one rejection event, and 37% of the eyes with a rejection event had graft failure.[6]

Corneal graft rejection is the most common cause of graft failure in the late postoperative period.[2] The reported incidence of graft rejection is lower in endothelial keratoplasty. Descemet membrane endothelial keratoplasty (DMEK) has been reported to have a rejection rate as low as 0.7% at one year in one series, but other studies have reported higher rates.[7, 8]

Mortality/Morbidity

Corneal graft rejection is the most common cause of graft failure in the late postoperative period.

Race

No difference in corneal graft rejection between different races is known.

Sex

No sex predilection for corneal graft rejection is known.

Age

Host age may influence the risk of corneal graft rejection. Some investigators have concluded that hosts older than 60 years have a lower risk of corneal graft rejection, although this has not been confirmed. The effect of donor age on corneal graft survival has been debated. The Cornea Donor Study did not find an association between donor age and corneal graft survival among corneal transplants at moderate failure risk.[9] Infants have higher rates of graft rejection than adults.

Prognosis

The sooner an episode of graft rejection is detected clinically and therapy is begun, the better the prognosis for graft survival. The rate of reversal of corneal endothelial graft rejection has been reported from 50-91%, depending on the clinical setting. In general, the prognosis is good if therapy is immediately instituted.

Depending on the degree of irreversible damage to the graft endothelium, even markedly edematous grafts may clear again. Once endothelial destruction has progressed to the point where the remaining endothelial function is inadequate to maintain deturgescence, the graft fails and becomes irreversibly edematous. Unfortunately, the endothelium has no or at best a very limited capacity for repair through mitosis.

Patient Education

No symptoms are related universally to graft rejection.

Astute patients may complain of a decrease in visual acuity, redness, pain, irritation, and photophobia. Patients may also be asymptomatic.

Any patient with a corneal graft should be instructed to seek ophthalmologic care urgently if these symptoms persist for more than a few hours.

History

Diagnosis of corneal graft rejection should be made only in grafts that have remained clear for at least 2 weeks following keratoplasty. By observing this guideline, graft rejection can be easily distinguished from other causes of graft failure that are more common in the early postoperative period (eg, primary donor failure). A sensitized host may rarely exhibit immunologic graft rejection before this 2-week period. Graft rejection has been observed to occur as late as 20 years after transplantation. Incidence of graft rejection is greatest in the first year following transplantation. A study of corneal graft surgery in the UK from 1999 to 2009 found endothelial failure as the most frequent indication for keratoplasty.[10]

No symptoms are related universally to corneal graft rejection, although astute patients may complain of the following:

Depending on the severity of the graft rejection, patients may be asymptomatic. Any patient with a corneal graft should be instructed to seek ophthalmologic care if these symptoms occur for more than a few hours.

Physical

Animal models of graft rejection reveal that the 3 corneal layers, epithelium, stroma, and endothelium, can be rejected separately. Although these separate rejection processes have been observed in humans, many patients present with combinations of epithelial, stromal, and endothelial rejection.

Epithelial rejection

Epithelial rejection presents in one of two manners.

The first type is characterized by an irregular, elevated epithelial rejection line that stains with fluorescein or rose bengal. The rejection line progresses rapidly across the cornea over several days to 2 weeks. A variant of this presentation may occur in which the epithelial rejection line takes the form of a ring, concentric with the limbus, which begins peripherally at the graft-host junction and progresses by shrinking centrally to a point. The rejection line represents a region of destruction of donor epithelium; the resulting epithelial defect is covered by host epithelium that grows inward from the remaining host cornea and limbus to cover the graft.

The second type of epithelial rejection is characterized by the presence of subepithelial infiltrates. These infiltrates consist of leukocytes and frequently have an appearance similar to the subepithelial infiltrates seen in adenoviral keratoconjunctivitis. These lesions may change location and shape over time, and they generally disappear on their own after several weeks.

Both types of epithelial rejection are steroid responsive, but, in many cases, the patient is either asymptomatic or has symptoms only of minimal irritation. As a result, the patient may not present to the ophthalmologist during these episodes. Although epithelial rejection generally is self-limited and tends not to cause visual disturbance on its own, it should be treated when found on examination as it may herald a more severe endothelial rejection.

Stromal rejection

Generally, stromal rejection in humans accompanies endothelial rejection and is difficult to demonstrate alone. It is characterized by peripheral full-thickness haze with limbal injection in a previously clear graft. An arc-shaped infiltrate may be noted peripherally at the graft-host junction that progresses centrally.

Endothelial rejection

Classic endothelial rejection presents with an endothelial rejection line (Khodadoust line) that usually begins at a vascularized portion of the peripheral graft-host junction and progresses, if untreated, across the endothelial surface over several days. The rejection line consists of mononuclear white cells that damage endothelial cells as the line sweeps across the endothelium.

Generally, a mild-to-moderate anterior chamber reaction is present. The damaged endothelium is unable to properly dehydrate the corneal graft; as a result, the donor cornea is clear ahead of the rejection line and is cloudy and edematous behind it.

A second variant of endothelial rejection is more diffuse in character, with scattered keratic precipitates and an anterior chamber reaction indicative of endothelial rejection and damage. In this type of endothelial rejection, stromal edema is typically not localized, but rather generalized throughout the graft, consistent with the generalized endothelial damage. The combination of keratic precipitates, an anterior chamber reaction, circumcorneal injection, and regions of corneal edema should be diagnosed as corneal graft rejection. In some cases, it may be difficult to distinguish graft edema from rejection and graft edema from endothelial insufficiency. Because rejection may be reversible, treating patients as if they have graft rejection is best.[11]

Allograft rejection after DMEK

Allograft rejection after DMEK may have a different clinical course with a slower onset than after penetrating keratoplasty.[12]

Causes

A great deal of energy has been expended in trying to determine clinical risk factors for corneal graft rejection. Because corneal graft rejection is the leading cause of graft failure in the late postoperative period, being able to identify and treat those patients at highest risk for graft rejection is important. Unfortunately, patients undergoing corneal transplantation represent a heterogeneous population, and proving that certain factors uniformly increase the risk of graft rejection is difficult. Differences in study designs exacerbate these difficulties.

Risk factors for corneal graft rejection can be divided into host and donor risk factors.

Potential host risk factors include the following:

Potential donor risk factors include the following:

One factor that has been decidedly proven to increase the risk of rejection is host corneal vascularization. Multiple studies have confirmed an increased risk of corneal graft rejection with increasing host vascularization, ranging from rates of 0-10% of graft rejection in avascular host corneas to rates of up to 25-50% in severely vascularized host corneas. The precise cause for this increased risk is believed to be the relative loss of immune privilege that accompanies the usually avascular central cornea.

Some of the risk factors listed above remain in some dispute. In some cases, multiple studies have yielded contradictory results, whereas, in other cases, an insufficient number of clinical studies exist. In all cases, these risk factors are modified by the particular clinical situation. In particular, studies regarding the role of the major histocompatibility complex and HLAs have yielded contradictory data, although several studies indicate a trend toward a decreased incidence of graft rejection occurring in matched corneal grafts. Currently, corneal grafts are not routinely HLA typed and matched in the United States, unlike other organ transplants. Further evidence is needed to justify the added cost and complexity of performing HLA typing prior to corneal transplantation.

The effect of donor age on corneal graft survival has been debated. The Cornea Donor Study did not find an association between donor age and corneal graft survival among corneal transplants at moderate failure risk.[9] Graft rejection rates are higher in infants than in adults.

Laboratory Studies

Graft failure is a clinical diagnosis; no laboratory studies are useful in diagnosis.

Imaging Studies

Graft failure is a clinical diagnosis; no imaging studies are useful in diagnosis.

Other Tests

Specular endothelial microscopy can be performed to determine endothelial cell density, pleomorphism, and polymegethism.

Pachymetry can be performed to measure corneal thickness.

Medical Care

Treatment of graft rejection depends on the type of rejection; however, in all cases, topical corticosteroids are the mainstay of treatment. Epithelial or stromal rejection without endothelial involvement usually does not progress to graft failure. As previously noted, epithelial rejection may be a self-limited process. Nonetheless, epithelial and stromal rejection should be aggressively treated, because they indicate host immunologic recognition of the graft and may precede a more severe endothelial rejection. Topical corticosteroids (eg, dexamethasone 0.1%, prednisolone acetate 1%) are prescribed 4-6 times/d until the signs of rejection resolve, followed by a slow tapering of the topical medication. These patients should be followed closely to be certain that the signs of rejection are improving and that endothelial rejection has not developed.

In cases of endothelial rejection, treatment must be more aggressive if the episode is to be reversed. Topical corticosteroids should be used every hour while awake and as frequently as possible at night for 2-3 days, followed by every 2 hours while awake. Steroid ointment may be used at bedtime. Therapy should be continued until signs of rejection resolve. Topical medications should be tapered slowly over several weeks to a few months depending upon the patient's response to treatment. Therapy should be continued for at least 4 weeks in the absence of response before judging that the graft has failed.

Other routes of administration of corticosteroids can be used in more severe endothelial rejections, in recurrent rejections, or if the patient is at high risk (eg, alkali burns, patients with vascularized corneas). Corticosteroids may be given by subconjunctival injection (eg, dexamethasone phosphate 2 mg, betamethasone 3 mg in 0.5 mL). A less painful alternative is a collagen shield soaked in corticosteroids and applied to the cornea combined with frequent corticosteroid eye drops. The collagen shield results in a higher local concentration of steroid than can be obtained by the use of corticosteroid drops alone. The shield acts as a depot reservoir for the drug that slowly releases its contents during the period between topical applications. Higher steroid concentrations have been noted in the cornea, aqueous humor, iris, and vitreous, compared with hourly drops alone.

Systemic corticosteroids can also be used in cases of severe endothelial rejection. Oral prednisone is generally started at dosages of 60-80 mg daily and continued for as long as 1-2 weeks before tapering. In line with findings in other fields of medicine, data suggest that pulsed intravenous (IV) steroids may be more effective than oral prednisone in reversing corneal graft rejection. Pulsed steroids (a single IV administration of 500 mg methylprednisolone) have been shown to improve the percentage of graft survival compared with oral steroids in patients who present early (within the first 8 days) in a rejection episode. A nonsignificant trend toward improved survival in all episodes of rejection in favor of pulsed steroids exists. In addition, pulsed steroids reduce the risk of subsequent rejection episodes, which may be a significant benefit in higher risk corneal grafts. Pulsed steroids also avoid prolonged administration of oral steroids.

In all cases of rejection, intraocular pressure should be monitored closely, especially when frequent corticosteroids are used. If necessary, elevated intraocular pressure should be controlled by topical medications to prevent glaucoma and to improve the chance of graft survival.

Surgical Care

No surgical care has proven beneficial during an episode of acute graft rejection.

Some transplant surgeons scrape the donor corneal epithelium to reduce the antigen load.

No solid evidence suggests that removing the donor epithelium is beneficial in reducing the risk of subsequent graft rejection.

If an acute graft rejection episode progresses to graft failure, repeat corneal transplantation may be indicated, including penetrating keratoplasty or endothelial keratoplasty.

Diet

No dietary restrictions have been identified.

Activity

No activity restrictions have been noted.

Complications

Depending on the degree of injury sustained by the graft, graft rejection episodes can progress to graft failure due to rejection.

Long-Term Monitoring

Patients should receive close follow-up care with an ophthalmologist for corneal graft rejection.

Frontiers in Corneal Graft Rejection Therapy

Systemic immunosuppression with cyclosporine in high-risk corneal transplantation has yielded varying results.[13] Cyclosporin A is a potent immunosuppressive agent that has revolutionized transplant therapy by reducing rejection in heart, kidney, liver, and other organ transplants. Cyclosporine is a fungal protein that has a high degree of specificity for T-cell lymphocytes and inhibits T-cell–mediated immune responses. In some studies, systemic cyclosporin A (blood levels 130-170 mcg/L) has been shown to greatly increase the rate of graft survival in high-risk corneal transplantation when used prophylactically for 12 months following transplantation. Cyclosporin A therapy carries known significant risks, including hypertension, renal toxicity, hepatotoxicity, and neurotoxicity; it should be used only after a thorough medical evaluation. Careful postoperative monitoring is essential and is generally best completed in conjunction with other physicians.

Topical administration of cyclosporin A also has been examined[15] and has yielded conflicting results for both prophylaxis and treatment of graft rejection episodes. Substitution of topical cyclosporine for topical corticosteroids may decrease intraocular pressure in cases of postkeratoplasty ocular hypertension or glaucoma but result in an increased risk of graft rejection.[16, 17] Cyclosporin A is not readily able to penetrate the corneal epithelium. Differences in drug vehicle and corneal penetration may account for the different outcomes seen in the use of topical cyclosporin A. Interestingly, collagen shields impregnated with cyclosporin A increase the corneal penetration of cyclosporine and can successfully reverse graft rejection in rabbits. Although methods that improve corneal penetration of cyclosporin A may improve its efficacy, they also may increase its potential systemic adverse effects. Note that blood levels of cyclosporin A have been recorded after topical administration of cyclosporin A in olive oil.

Other potential agents in the treatment of corneal graft rejection include antimetabolites (eg, azathioprine, 6-mercaptopurine) and immunosuppressives (eg, tacrolimus [FK-506], rapamycin). Relatively few studies have been performed using these agents in corneal transplantation, and their role in corneal transplantation therapy has yet to be determined. Each of these medications is associated with significant systemic adverse effects.

Tacrolimus has received more study than the other agents. One group in England reported significant success in preventing and reversing corneal and limbal allograft rejection in high-risk eyes.[18, 19] They found that no patient with therapeutic levels of tacrolimus suffered irreversible graft rejection. Several patients suffered from systemic adverse effects, including irreversible renal failure. In the United States, tacrolimus has only rarely been used in the setting of corneal transplantation. In another study of patients with high-risk corneal transplants treated with systemic tacrolimus, 65% had clear grafts at 2 years.[20] Topical tacrolimus has also been used successfully for the treatment of graft rejection.[21]

One significant issue is that the cost of tacrolimus for this indication is not always covered.

Medication Summary

Corticosteroids are the mainstay of treatment of acute graft rejection. They can be given topically, via subconjunctival injection, or systemically.

Prednisolone acetate 1% (Omnipred, Pred Forte)

Clinical Context:  Most commonly used topical corticosteroid. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Dexamethasone (Decadron)

Clinical Context:  For various allergic and inflammatory diseases. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. Also used for subconjunctival injections.

Prednisone (Deltasone, Rayos)

Clinical Context:  May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Methylprednisolone (Solu-Medrol, Medrol, Depo-Medrol)

Clinical Context:  Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Single pulsed dose of IV steroids prior to PO steroids may improve final outcome.

Class Summary

These agents provide anti-inflammatory activity to suppress the natural immune response that leads to acute graft rejection.

Tacrolimus (Astagraf XL, Envarsus XR, Prograf)

Clinical Context:  Tacrolimus suppresses humoral immunity (T-cell activity). It is a calcineurin inhibitor with 2-3 times the potency of cyclosporine. Tacrolimus can be used at lower doses than cyclosporine can, but it has severe adverse effects, including renal dysfunction, diabetes, and pancreatitis. Levels are adjusted according to renal function, hepatic function, and adverse effects.

Cyclosporine (Gengraf, Neoral, Sandimmune)

Clinical Context:  Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-versus-host disease for various organs.

Class Summary

Agents in this category inhibit key factors involved in the immune response. They may be used when graft rejection is not controlled adequately by systemic corticosteroids. 

Author

Michael Taravella, MD, Director of Cornea and Refractive Surgery, Rocky Mountain Lions Eye Institute; Professor, Department of Ophthalmology, University of Colorado School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: J&J Vision (Consultant)/Proctor<br/> for: Coronet Surgical (Consultant), no income received.

Coauthor(s)

William G Gensheimer, MD, Capt, USAF, Ophthalmologist, Warfighter Eye Center, Malcolm Grow Medical Clinics and Surgery Center, Joint Base Andrews

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Sidney Kimmel Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Hospital

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cornea Society, AAO, OMIC, Avedro; Bio-Tissue; GSK, Kala, Novartis; Shire; Sun Ophthalmics; TearLab<br/>Serve(d) as a speaker or a member of a speakers bureau for: Avedro; Bio-Tissue; Shire<br/>Received income in an amount equal to or greater than $250 from: AAO, OMIC, Avedro; Bio-Tissue; GSK, Kala, Novartis; Shire; Sun Ophthalmics; TearLab.

Chief Editor

Hampton Roy, Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Jack L Wilson, PhD, Distinguished Professor, Department of Anatomy and Neurobiology, University of Tennessee Health Science Center College of Medicine

Disclosure: Nothing to disclose.

References

  1. Eye Bank Association of America 2016 Eye Banking Statistical Report. Available at http://www.restoresight.org/wp-content/uploads/2015/03/2014_Statistical_Report-FINAL.pdf. Accessed: October 15, 2018.
  2. Tan DT, Dart JK, Holland EJ, Kinoshita S. Corneal transplantation. Lancet. 2012 May 5. 379(9827):1749-61. [View Abstract]
  3. Jabbehdari S, Rafii AB, Yazdanpanah G, Hamrah P, Holland EJ, Djalilian AR. Update on the Management of High-Risk Penetrating Keratoplasty. Curr Ophthalmol Rep. 2017 Mar. 5 (1):38-48. [View Abstract]
  4. Ritter T, Wilk M, Nosov M. Gene therapy approaches to prevent corneal graft rejection: where do we stand?. Ophthalmic Res. 2013. 50(3):135-40. [View Abstract]
  5. Panda A, Vanathi M, Kumar A, Dash Y, Priya S. Corneal graft rejection. Surv Ophthalmol. 2007 Jul-Aug. 52 (4):375-96. [View Abstract]
  6. Stulting RD, Sugar A, Beck R, Belin M, Dontchev M, Feder RS, et al. Effect of donor and recipient factors on corneal graft rejection. Cornea. 2012 Oct. 31 (10):1141-7. [View Abstract]
  7. Ang M, Wilkins MR, Mehta JS, Tan D. Descemet membrane endothelial keratoplasty. Br J Ophthalmol. 2016 Jan. 100 (1):15-21. [View Abstract]
  8. Guerra FP, Anshu A, Price MO, Giebel AW, Price FW. Descemet's membrane endothelial keratoplasty: prospective study of 1-year visual outcomes, graft survival, and endothelial cell loss. Ophthalmology. 2011 Dec. 118 (12):2368-73. [View Abstract]
  9. Cornea Donor Study Investigator Group, gal RL, Dontchev M, Beck RW, Mannis MJ, Holland EJ, et al. The effect of donor age on corneal transplantation outcome results of the cornea donor study. Ophthalmology. 2008 Apr. 115 (4):620-626.e6. [View Abstract]
  10. Keenan TD, Jones MN, Rushton S, Carley FM. Trends in the indications for corneal graft surgery in the United Kingdom: 1999 through 2009. Arch Ophthalmol. 2012 May 1. 130(5):621-8. [View Abstract]
  11. Lee HS, Kim MS. Influential factors on the survival of endothelial cells after penetrating keratoplasty. Eur J Ophthalmol. 2009 Nov-Dec. 19(6):930-5. [View Abstract]
  12. Monnereau C, Bruinsma M, Ham L, Baydoun L, Oellerich S, Melles GR. Endothelial cell changes as an indicator for upcoming allograft rejection following descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2014 Sep. 158 (3):485-95. [View Abstract]
  13. Coster DJ, Williams KA. The impact of corneal allograft rejection on the long-term outcome of corneal transplantation. Am J Ophthalmol. 2005 Dec. 140 (6):1112-22. [View Abstract]
  14. Sel S, Schlaf G, Schurat O, Altermann WW. A novel ELISA-based crossmatch procedure to detect donor-specific anti-HLA antibodies responsible for corneal allograft rejections. J Immunol Methods. 2012 Jul 31. 381(1-2):23-31. [View Abstract]
  15. Bertelmann E, Pleyer U. Immunomodulatory therapy in ophthalmology - is there a place for topical application?. Ophthalmologica. 2004 Nov-Dec. 218(6):359-67. [View Abstract]
  16. Perry HD, Donnenfeld ED, Kanellopoulos AJ, Grossman GA. Topical cyclosporin A in the management of postkeratoplasty glaucoma. Cornea. 1997 May. 16 (3):284-8. [View Abstract]
  17. Perry HD, Donnenfeld ED, Acheampong A, Kanellopoulos AJ, Sforza PD, D'Aversa G, et al. Topical Cyclosporine A in the management of postkeratoplasty glaucoma and corticosteroid-induced ocular hypertension (CIOH) and the penetration of topical 0.5% cyclosporine A into the cornea and anterior chamber. CLAO J. 1998 Jul. 24 (3):159-65. [View Abstract]
  18. Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the management of high-risk corneal and limbal grafts. Ophthalmology. 2001 Oct. 108(10):1838-44. [View Abstract]
  19. Magalhaes OA, Marinho DR, Kwitko S. Topical 0.03% tacrolimus preventing rejection in high-risk corneal transplantation: a cohort study. Br J Ophthalmol. 2013 Nov. 97(11):1395-8. [View Abstract]
  20. Joseph A, Raj D, Shanmuganathan V, Powell RJ, Dua HS. Tacrolimus immunosuppression in high-risk corneal grafts. Br J Ophthalmol. 2007 Jan. 91 (1):51-5. [View Abstract]
  21. Ghaffari R, Ghassemi H, Zarei-Ghanavati M, Latifi G, Dehghani S, Haq Z, et al. Tacrolimus Eye Drops as Adjunct Therapy in Severe Corneal Endothelial Rejection Refractory to Corticosteroids. Cornea. 2017 Oct. 36 (10):1195-1199. [View Abstract]
  22. Boisjoly HM, Tourigny R, Bazin R, Laughrea PA, Dube I, Chamberland G, et al. Risk factors of corneal graft failure. Ophthalmology. 1993 Nov. 100(11):1728-35. [View Abstract]
  23. Chen YF, Gebhardt BM, Reidy JJ, Kaufman HE. Cyclosporine-containing collagen shields suppress corneal allograft rejection. Am J Ophthalmol. 1990 Feb 15. 109(2):132-7. [View Abstract]
  24. Hegde S, Beauregard C, Mayhew E. CD4(+) T-cell-mediated mechanisms of corneal allograft rejection: role of Fas-induced apoptosis. Transplantation. 2005 Jan 15. 79(1):23-31. [View Abstract]
  25. Hill JC. Systemic cyclosporine in high-risk keratoplasty. Short- versus long-term therapy. Ophthalmology. 1994 Jan. 101(1):128-33. [View Abstract]
  26. Hill JC. The use of cyclosporine in high-risk keratoplasty. Am J Ophthalmol. 1989 May 15. 107(5):506-10. [View Abstract]
  27. Hill JC, Maske R, Watson P. Corticosteroids in corneal graft rejection. Oral versus single pulse therapy. Ophthalmology. 1991 Mar. 98(3):329-33. [View Abstract]
  28. Hwang DG, Stern WH, Hwang PH, MacGowan-Smith LA. Collagen shield enhancement of topical dexamethasone penetration. Arch Ophthalmol. 1989 Sep. 107(9):1375-80. [View Abstract]
  29. Khodadoust AA, Silverstein AM. Transplantation and rejection of individual layers of the cornea. Investigative Ophthalmologic and Visual Sciences. Vol 8.: 180-195.
  30. Reidy JJ, Gebhardt BM, Kaufman HE. The collagen shield. A new vehicle for delivery of cyclosporin A to the eye. Cornea. 1990 Jul. 9(3):196-9. [View Abstract]
  31. Smolin G, Thoft RA. The cornea. Scientific Foundations and Clinical Practice. 3rd ed. Lippincott William & Wilkins; 1994.
  32. Wang M, Lin Y, Chen J, Liu Y, Xie H, Ye C. Studies on the effects of the immunosuppressant FK-506 on the high-risk corneal graft rejection. Yan Ke Xue Bao. 2002 Sep. 18(3):160-4. [View Abstract]
  33. Wilson SE, Kaufman HE. Graft failure after penetrating keratoplasty. Surv Ophthalmol. 1990 Mar-Apr. 34(5):325-56. [View Abstract]

This severely vascularized cornea would be at high risk for graft rejection following a penetrating keratoplasty. This patient experienced Stevens-Johnson syndrome.

This is an example of an acute graft rejection episode. Note the graft edema, Descemet folds, and keratic precipitates.

This severely vascularized cornea would be at high risk for graft rejection following a penetrating keratoplasty. This patient experienced Stevens-Johnson syndrome.

This is an example of an acute graft rejection episode. Note the graft edema, Descemet folds, and keratic precipitates.