Elsevier

Survey of Ophthalmology

Volume 52, Issue 4, July–August 2007, Pages 375-396
Survey of Ophthalmology

Major Review
Corneal Graft Rejection

https://doi.org/10.1016/j.survophthal.2007.04.008Get rights and content

Abstract

Penetrating keratoplasty is the most widely practiced type of transplantation in humans. Irreversible immune rejection of the transplanted cornea is the major cause of human allograft failure in the intermediate and late postoperative period. This immunological process causes reversible or irreversible damage to the grafted cornea in several cases despite the use of intensive immunosuppressive therapy. Corneal graft rejection comprises a sequence of complex immune responses that involves the recognition of the foreign histocompatibility antigens of the corneal graft by the host's immune system, leading to the initiation of the immune response cascade. An efferent immune response is mounted by the host immune system against these foreign antigens culminating in rejection and graft decompensation in irreversible cases. A variety of donor- and host-related risk factors contribute to the corneal rejection episode. Epithelial rejection, chronic stromal rejection, hyperacute rejection, and endothelial rejection constitute the several different types of corneal graft rejection that might occur in isolation or in conjunction. Corneal graft failure subsequent to graft rejection remains an important cause of blindness and hence the need for developing new strategies for suppressing graft rejection is colossal. New systemic pharmacological interventions recommended in corneal transplantation need further evaluation and detailed guidelines. Two factors, prevention and management, are of significant importance among all aspects of immunological graft rejection. Preventive aspects begin with the recipient selection, spread through donor antigenic activity, and end with meticulous surgery. Prevention of corneal graft rejection lies with reduction of the donor antigenic tissue load, minimizing host and donor incompatibility by tissue matching and suppressing the host immune response. Management of corneal graft rejection consists of early detection and aggressive therapy with corticosteroids. Corticosteroid therapy, both topical and systemic, is the mainstay of management. Addition of immunosuppressive to the treatment regimen helps in quick and long term recovery. Knowledge of the immunopathogenesis of graft rejection may allow a better understanding of the immunological process thus helping in its prevention, early detection and management.

Introduction

Although corneal transplantation has been performed for over a century, it has shown a dramatic increase since the 1960s.20, 22, 25, 138, 160, 198 It has evolved from its primitive form to the present day surgery due to improved eye banking procedures, technical improvement in the form of good suturing material, higher optical quality microscopes, and better drugs to suppress postoperative inflammation. All these factors have improved the outcome of the corneal transplant surgery and they are also helpful in appreciating the cause of graft failure, either primary or secondary.138 Graft rejection is one of the leading causes of corneal graft failure. With the introduction of topical steroids and other immuno-suppressive drugs, the graft survival rate has remarkably improved.7 Extensive research continues into the subject of corneal graft rejection and the need for preventing allograft rejection and improving graft survival following rejection is paramount.

Section snippets

Definition

First described by Paufique et al in 1948,160 later by Maumenee (1951),105 and later elaborated by Khodadoust and Silverstein in 1969,89 corneal graft rejection is a specific process in which a graft that has been clear for at least 2 weeks suddenly succumbs to graft edema in conjunction with anterior segment inflammatory signs.91, 109, 138 This process is immunologically mediated and represents the end stage of immunological reaction that maybe lead to reversible/ irreversible graft damage.

Incidence

About 60,000 corneal grafts are performed every year worldwide, of which up to 30% of eyes with penetrating keratoplasty experience at least one episode of rejection and about 5–7% lead to eventual graft failure.1, 34, 104, 132 Rate of rejection episodes vary widely in several studies. Reported incidence of corneal graft rejection varies from 2.3% to 68%.160 About, 12% of graft rejection cases in patients with good prognostic keratoplasty and 40% in complicated cases have been reported to lead

Mechanism of Rejection

Corneal grafts have a higher success rate than other forms of organ transplantation. The low incidence of graft rejection in keratoplasty despite human leucocyte antigen (HLA)-matching of donor and recipient not being done as a routine in several keratoplasty centers is impressive. The major findings regarding corneal allograft rejection in experimental animals have been extensively reviewed.45, 146, 147, 204, 207 The corneal graft rejection is a complex immune process consisting of sequence of

Risk Factors

The various factors influencing graft rejection have been widely reported.19, 66, 73, 91, 93, 100, 106, 109, 143, 194, 195

Classification

All the three layers of the cornea, (epithelium, stroma, and endothelium) can undergo rejection.89 Corneal graft rejection (Fig. 1) can be classified as epithelial rejection, chronic stromal rejection, hyperacute stromal rejection, chronic focal rejection, or endothelial rejection, combined stromal and endothelial rejection, and rejection in a repeat graft (Table 2).4, 23, 84, 89, 92, 104, 139, 160

Epithelial Rejection

In epithelial rejection, the eye is generally quiet, asymptomatic, or mildly inflamed. Its exact incidence is hard to determine because of its asymptomatic nature; it is reported to be 10–14%.23, 89, 160

Differential Diagnosis of Corneal Graft Rejection

There are a number of conditions that may mimic an immune rejection160 and can be confused with graft rejection (Table 4): late graft failure, sterile/infectious endophthalmitis in a grafted cornea, epithelial downgrowth, recurrent herpetic keratitis in a graft, and infectious crystalline keratopathy.116

Prevention

Prevention of immune-mediated graft rejection can be considered with relevance to preoperative, intraoperative, and postoperative factors. Preoperative measures towards preventing immune mediated allograft rejection are achieved by minimizing antigenic difference between the host and the donor tissue and reducing the antigenic load of donor tissue.

Intraoperative factors that contribute to prevention of corneal graft rejection consist of a meticulous surgical technique, including of avoiding

Management (Tables 5 and 6)

Immunological rejection in a transplanted cornea may lead to human corneal allograft failure. Successful management requires early detection and aggressive therapy. Thus, it is mandatory to forewarn the patients with corneal graft to report at the onset of the early symptoms and signs of graft rejection such as decreased vision, pain and redness,138, 170 and a reduction in the visual acuity. Although actual management is dependent on the type of rejections, knowledge about the different drugs'

Corneal Graft Outcomes

Literature reports on corneal graft rejection reveal that graft prognosis is dependant on a variety of factors, such as preoperative case selection, preoperative measures for donor, intraoperative approach,early detection, type of rejection, and mode of management.9, 23, 27, 28, 83, 86, 104, 117, 165, 170, 186, 202 Visual outcome and graft survival after corneal transplantation is also greatly influenced by type of graft rejection.

Aldredge and Krachmer4 found that 76% of grafts with endothelial

Summary

Meticulous preoperative patient selection, patient education, and free discussion between patient and surgeon both pre- and postoperatively are important parameters for both prevention and management of graft rejection reaction. The sequelae of inflammation, whether occurring before corneal transplantation or subsequently, profoundly influence the predisposition to graft rejection. Of the developments that have been instrumental in reducing rejection in vascularized organ transplantation,

Method of Literature Search

The Medline database was searched electronically in English language for the years 1950–2005 with the keywords corneal graft rejection and corneal allograft rejection. Some articles that were not found by our Medline search were taken from the references from other articles and books. Inclusion of the articles was based on their importance to the subject while exclusion was used to avoid redundancy.

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