This article is more than 5 years old. Information may no longer be current.
Treating inflammation is crucial in preventing graft rejection and failure post-PKP
Long-term data show that corneal allograft rejection does occur and is directly correlated with time.
Click Here to Manage Email Alerts
Topical corticosteroids have a primary role in preventing and treating graft rejection after penetrating keratoplasty (PKP). By reducing inflammation, they block the cascade of biochemical events that, through neutralizing the immune privilege of the cornea, lead to irreversible graft failure.
“Graft rejection is the immune system’s response to chronic inflammation. Chronic inflammation always has an immune component,” said Leonardo Mastropasqua, MD,director of the Regional Center of Excellence in Ophthalmology at the University G. D’Annuzio Chieti-Pescara in Chieti, Italy.
Inflammation predisposes the graft to rejection
 | “Graft rejection is the immune system’s response to chronic inflammation. Chronic inflammation always has an immune component." —Leonardo Mastropasqua, MD |
The immune privilege of corneal grafts depends on the inhibition or disruption of the immune response at all three levels (afferent, central, and efferent) of the immune reflex arch and is mainly correlated to the avascularity of the cornea.
“Thanks to this privilege, first-time recipients of corneal allografts can expect a 90% success rate, without the aid of tissue typing or systemic immunosuppression,” Dr. Mastropasqua said.
However, in rejection-prone corneal allografts, the antigen produced by antigen presenting cells (APC) can penetrate the conjunctival-associated lymphoid tissue and the draining lymph nodes of the face and neck, leading to T cell activation, proliferation, and expansion. Through the efferent lymphatic channels, effector cells carry the antigen to the corneal cells, leading to graft destruction.
Long-term data show that corneal allograft rejection does occur and is directly correlated with time.
“The 86% graft survival rate of PKP at 1 year decreases to 55% at 15 years,” Dr. Mastropasqua said. “In addition, although we have improved our diagnostic and therapeutic armamentarium, survival rate has remained basically the same over the past 15 years.”
The predictive variables of graft failure are numerous, and are mainly correlated with preoperative diagnosis; the number of grafts; individual responses to transplantation, particularly inflammation, neovascularization, and increased IOP; the number of rejection episodes; and the presence and modality of immunosuppressive therapy.
Long-term data show that rejection remains the first cause of graft failure and that the sequelae of inflammation, whether occurring before or after corneal transplantation, profoundly influence the outcomes of PKP by predisposing the graft to rejection.
Dr. Mastropasqua explained that inflammation neutralizes the immune privilege of the cornea, activating the antigen and the cascade of events that leads to rejection. Inflammation also causes neovascularization, which triggers graft failure.
“The quickest way to rejection is operating on an inflamed eye,” Dr. Mastropasqua pointed out.
Better than slit-lamp examination, confocal microscopy can help detect the presence and distribution of dendritic cells in the cornea.
“Whereas in a healthy eye, dendritic cells are mostly present at the limbus, in an inflamed eye they migrate toward the center of the cornea where they are overexpressed,” he explained.
Inflammation must be identified and categorically suppressed before PKP. This will generally prevent the immune response and the formation of new vessels, giving graft survival a better chance.
Prevention and treatment of graft rejection
Before surgery, and in the early postoperative days, patients should also be differentiated according to their risk of rejection. Low-risk patients are first graft patients with avascular cornea, normal IOP, a healthy epithelium, and no inflammation. A history of inflammation, of variable intensity and extension, is a parameter of middle- and high-risk patients, who will develop an inflammatory and neovascular response to surgery in the vast majority of cases. Multiple graft patients, and patients with previous episodes of rejection are always classified as high-risk candidates.
“Both prevention and treatment of graft rejection are correlated with the patient’s risk category,” Dr. Mastropasqua said.
| “Topical steroids prevent allograft rejection by inhibiting leukocyte migration into the cornea. They block the efferent arm of the immune response.” —Leonardo Mastropasqua, MD |  |
Low-risk patients should be treated for prevention with topical corticosteroids. Dr. Mastropasqua suggested a schedule of 4 times daily, tapered over 6 months. A mild steroid therapy regimen with a single daily administration should be maintained indefinitely.
“Topical steroids prevent allograft rejection by inhibiting leukocyte migration into the cornea. In other words, they block the efferent arm of the immune response,” he explained.
High-risk patients require adjunctive therapy with systemic steroids. Calcineurin blockers such as cyclosporin and tacrolimus should also be used to inhibit the “decision-making” phase of the immune reflex arch, ie, T cell activation, proliferation, and clonal expansion. According to Dr. Mastropasqua, topical administration of these drugs has proven less effective than systemic administration in prolonging graft survival.
In the treatment of graft rejection, topical corticosteroids are the gold standard, although the dosage, type, and route of administration have not been established by standardized protocols.
“Basically, the treatment depends upon the type of rejection,” Dr. Mastropasqua said.
In nonendothelial rejection, he suggested administering topical steroids 4 to 6 times a day for 1 week, tapered over 6 to 8 weeks. For mild endothelial rejection, administration should be every hour for the first 4 to 7 days, slowly tapered over 2 to 3 months. Severe endothelial rejection also requires hourly administration for 4 to 7 days, but an extended tapering over 3 to 4 months. Adjunctive treatment with systemic steroids and calcineurin blockers such as cyclosporin, mycophenolate mofetil, or tacrolimus is necessary in these patients.
The breakthrough of new steroids
Topical corticosteroids are required at all levels of prevention and treatment, but in the highly unstable, postcorneal transplant eye, they must be used for months, or even years. According to Dr. Mastropasqua, the most commonly used steroid drops are effective, but complications may arise with long-term use.
“What surgeons need to increase graft survival is a topical steroid that is effective in reducing ocular surface inflammation and vascularization without raising the intraocular pressure,” he said.
Increased IOP induced by common steroids is detrimental to the success of PKP because it can cause graft inflammation, thus reintroducing the original problem.
In a recent study of postpenetrating keratoplasty and postkeratolimbal allograft patients, loteprednol etabonate 0.5% was shown to decrease a steroid-induced IOP increase in known steroid responders by an average of 44.9% at week 39.
“New steroids, such as loteprednol etabonate, may be the answer we have been waiting for. Along with new modalities of treatment, such as monopolyclonal antibodies and gene therapy, they could help achieve safer PKP with increased graft survival rate,” he concluded.
For more information:
- Leonardo Mastropasqua, MD, is director of the Regional Center of Excellence in Ophthalmology at the University G. D’Annuzio Chieti-Pescara in Chieti, Italy. He can be reached at +39 0871 358 410, mastropa@unich.it.
References
- Holland EJ. Attenuation of ocular hypertension in steroid responders following corneal transplantation with the use of topical 0.5% loteprednol etabonate. In: Lotemax (loteprednol etabonate ophthalmic suspension 0.5%): A compendium of publications and abstracts. Refractive Eye Care for ophthalmologists 2004;8(10):4.
- Mastropasqua L, Nubile M, Lanzini M, et al. Epithelial dendritic cell distribution in normal and inflamed human cornea: in vivo confocal microscopy study. Am J Ophthalmol. 2006 Nov;142(5):736-744.