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Year : 1999  |  Volume : 47  |  Issue : 1  |  Page : 3-9

Corneal allograft rejection: Risk factors, diagnosis, prevention, and treatment

1 Department of Ophthalmology, Queen's Medical Centre, University Hospital, Nottingham, United Kingdom
2 Princess Alexandra Eye Pavilion Queen's Medical Centre, University Hospital, Nottingham, United Kingdom

Correspondence Address:
Harminder S Dua
B-Floor, South Block, Queen's Medical Centre, Nottingham NG72UH
United Kingdom
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Source of Support: None, Conflict of Interest: None

PMID: 16130277

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Recent advances in corneal graft technology, including donor tissue retrieval, storage and surgical techniques, have greatly improved the clinical outcome of corneal grafts. Despite these advances, immune mediated corneal graft rejection remains the single most important cause of corneal graft failure. Several host factors have been identified as conferring a "high risk" status to the host. These include: more than two quadrant vascularisation, with associated lymphatics, which augment the afferent and efferent arc of the immune response; herpes simplex keratitis; uveitis; silicone oil keratopathy; previous failed (rejected) grafts; "hot eyes"; young recipient age; and multiple surgical procedures at the time of grafting. Large grafts, by virtue of being closer to the host limbus, with its complement of vessels and antigen-presenting Langerhans cells, also are more susceptible to rejection. The diagnosis of graft rejection is entirely clinical and in its early stages the clinical signs could be subtle. Graft rejection is largely mediated by the major histocompatibility antigens, minor antigens and perhaps blood group ABO antigens and some cornea-specific antigens. Just as rejection is mediated by active immune mediated events, the lack of rejection (tolerance) is also sustained by active immune regulatory mechanisms. The anterior chamber associated immune deviation (ACAID) and probably, conjunctiva associated lymphoid tissue (CALT) induced mucosal tolerance, besides others, play an important role. Although graft rejection can lead to graft failure, most rejections can be readily controlled if appropriate management is commenced at the proper time. Topical steroids are the mainstay of graft rejection management. In the high-risk situations however, systemic steroids, and other immunosuppressive drugs such as cyclosporin and tacrolimus (FK506) are of proven benefit, both for treatment and prevention of rejection.

Keywords: Keratoplasty, allograft rejection, risk factors, prevention, treatment

How to cite this article:
Dua HS, Azuara-Blanco A. Corneal allograft rejection: Risk factors, diagnosis, prevention, and treatment. Indian J Ophthalmol 1999;47:3-9

How to cite this URL:
Dua HS, Azuara-Blanco A. Corneal allograft rejection: Risk factors, diagnosis, prevention, and treatment. Indian J Ophthalmol [serial online] 1999 [cited 2023 Jun 10];47:3-9. Available from: https://journals.lww.com/ijo/pages/default.aspx/text.asp?1999/47/1/3/22904

Keratoplasty is the most common form of human solid tissue transplantation. In most developed countries, the ready availability of donor material, adequate donor screening and storage facilities and refinements in surgical instrumentation and techniques have greatly improved the final visual outcome following corneal transplantation. Unlike other tissues and organs, corneal allo-transplantation usually does not require systemic and permanent immunosuppression. Nevertheless, allograft rejection is the leading cause of graft failure in corneal transplantation.[1],[2] It is estimated that approximately 10% of all grafts fail because of immunologic rejection. Around 18% of the graft recipients have at least one rejection episode. The rejection rate greatly increases in "high risk" corneal transplants (see below).

Although prompt diagnosis of a rejection episode and initiation of adequate therapy can abort the process and retain graft clarity in most cases, irreversible graft rejection leading to opacification continues to pose a clinical and immunological challenge. In this review we shall first examine the risk factors associated with graft rejection and the clinical signs and symptoms that aid in early diagnosis. We will then look at the immunological aspects that form the basis of the corneal graft rejection and finally describe and rationalise various preventive measures and treatment regimes.

  Risk Factors for Rejection Top

Host factors

Patients with corneal stromal vascularization have a high risk of immunological failure. The degree of vascularization (i.e., number of vessels and number of quadrants involved) is associated with both the risk of rejection and the time interval between penetrating keratoplasty and the onset of rejection. Allograft rejection is more likely with deep stromal vascularization. Once corneal rejection occurs, the difficulty of reversal also depends on the degree of corneal vascularization. Most authors consider stromal vascularization of two quadrants or more to be a high risk factor.[3][4][5][6][7] Vessels are usually associated with formation of lymphatics which augment the afferent arc of the immune response (see below). The risk of rejection is increased in regrafts, particularly when two or more grafts have previously failed.[6] It has been suggested that a previous graft failure from rejection is not itself a risk factor,[8] and that the higher incidence of rejection may result from the vascularization occurring in the rejection process. Positive donor-recipient crossmatch due to pre-existing lymphocytotoxic antibodies (by previous graft or by previous corneal rejection) and blood transfusions have been associated with an increased risk of corneal endothelial rejection.[9] Several pre-existing conditions such as uveitis, herpes simplex keratitis, atopic dermatitis and eczema (frequently seen in patients with keratoconus) are associated with a greater risk of immune reactions. Active inflammation and infection at the time of surgery greatly predisposes to corneal allograft rejection and also to graft failure due to nonimmunological causes. Other possible factors associated with an increased probability of graft rejection include previous anterior segment surgery other than penetrating keratoplasty, anterior iris synechiae, vitreous adhesions, and multiple surgeries at a time.[2][3][4][5][6] On the contrary, glaucoma is an important risk factor for graft failure due to non-immunological mechanisms, but does not predispose to rejection.

Demographic factors

It is accepted that young recipient age is associated with higher rate of failure from rejection,[6][7][8],[10] even though other series failed to identify age as an independent risk factor for rejection failure.[11] Sex of recipient and donor and cause of donor death do not influence graft failure due to rejection.[1],[6]

Technical factors

Larger grafts appear to increase the risk of graft rejection. [7,8] Theoretically, larger grafts might increase the risk of rejection by presenting a greater antigen load closer to the recipient limbal vasculature, and by containing more antigen-presenting cells. Interestingly, it has been reported also that smaller grafts are at increased risk of rejection failure than larger grafts.[6] This apparent contradiction is probably explained by a selection bias, as many surgeons preferentially use smaller grafts in high-risk eyes. Eccentric grafts probably have higher risk of rejection because they are close to the vascularised limbus and surrounded by host corneal tissue with abundant Langerhans cells (see below). Suture technique (interrupted, continuous or mixed sutures) is not likely to be associated with the risk of rejection. Silk should not be used because it induces an undesirable level of inflammation and vascularization. The most common material for running and interrupted suturing is 10-0 nylon, followed by 10-0 polypropylene and 11-0 nylon. When interrupted sutures are placed, excess suture is cut as close to the knot as possible. The knot is rotated into and buried just beneath the corneal surface in the donor stroma, because location of the knot in the host's stroma may attract vessels.

Other factors

Possible benefits of intermediate-term storage by organ culture in reducing rejection response have been suggested.[12] However, most studies have not found significant differences in rejection rate among the modalities of tissue storage.[2],[6],[13],[14] Time from death to enucleation, from enucleation to storage, and from storage to transplantation probably do not influence rejection rate, but may affect graft outcome. Rejection during and after pregnancy has been noted in almost all forms of transplantation,[15] and this process has been also noted among corneal transplant recipients.[16],[17] Although pregnancy is viewed as a state of relative immune suppression, allograft rejections still occur. Postpartum rejection episodes may be related to a return to normal immune responsiveness or to a rebound effect from reduced immunity during pregnancy. Anecdotally, influenza vaccination[18] has been associated with rejection episodes of corneal transplants.

  Clinical Features Top

Corneal graft rejection most commonly occurs during the first year after surgery. Not all episodes of rejection lead to immediate graft failure, although they acclerate postoperative loss of endothelial cells.[19] Several factors leading to intercurrent inflammation such as suture loosening, suture track infection, or recurrent herpetic infection, may precipitate a rejection episode. Graft rejection is associated with blurring of vision, redness of the eye and discomfort. However, in cases with mild rejection the patient may be asymptomatic.

There are several types of corneal graft rejection. These types may be associated in the same patient. Endothelial rejection is the most common form of graft rejection. Clinical signs include limbal injection, aqueous cells, keratic precipitates in the graft [Figure:1], and edema of the graft. An endothelial rejection line (i.e., Khodadoust line), associated with segmental corneal edema can be seen [Figure:2]. The rejection line starts in the periphery of the graft, usually in the vicinity of stromal vessels, and moves towards the centre of the graft. Comeal pachymetry can be used to follow the response to therapy of rejection after the initial acute phase. Irreversible endothelial rejection is associated with diffuse edema and opacity of the graft. Subepithelial nummular infiltrates are whitish infiltrates of 0.2 - 0.5 mm in diameter located in the anterior stroma [Figure:3]. This is the second.most common form of corneal graft rejection. They are morphologically similar to those seen after adenoviral conjunctivitis. Epithelial rejection is marked by the appearance of an elevated epithelial rejection line, representing a moving front of damaged donor epithelial cells. It is usually seen in the periphery and stains with fluorescein [Figure:4].[20] Stromal rejection is uncommon. It is characterised by peripheral stromal infiltrate and haze in a previously clear graft [Figure:5]. It usually occurs adjacent to an area of vascularization and simultaneously with endothelial rejection.

  Immunological Aspects Top

Corneal allografts can survive without systemic and permanent immunosuppressive treatment. This unique possibility appears to be due to a relative immune privilege. For decades, investigators believed that immune privilege resulted solely from a defect in the afferent limb of immune induction. The absence of vascularity and lymphatic vessels in the cornea and the integrity of the blood-ocular barrier interferes with both recognition of the allo-antigens in the graft and destruction by the immune system. However, there is evidence that prolonged corneal graft survival is sustained also by active immune regulatory mechanisms. Experimental studies have demonstrated that the injection of antigens into the anterior chamber induces a stereotypic pattern of immune response that has been termed Anterior Chamber Associated Immune Deviation (ACAID).[21],[22] An antigen placed in the anterior chamber (and also in the vitreous cavity and in the subretinal space) evokes a selective, long-lasting, systemic immune deficiency in which some immune cells are missing and at the same time other efferent immune reactions are generated.

The dominant antigenic stimulus for allograft rejection and antibody production are the HLA antigens. HLA antigens are determined by genes located in the short arm of the chromosome 6. There are two classes of HLA antigens, class I and II. HLA class I antigens are transmembrane glycoproteins designated HLA-A and HLA-B. HLA-I antigens are expressed on most nucleated cells and platelets, and stimulate T-cell proliferation and antibody production. HLA class II molecules (HLA-DR) consist of two linked transmembrane glycoprotein chains that are normally expressed on specifice immunocompetent antigen-presenting cells, such as tissue macrophages, corneal Langerhans cells, monocytes, B lymphocytes, and some activated T cells. Antigen-presenting cells play a central role in graft rejection. HLA-II antigens are recognised by CD4+ T-cells and are involved in the presentation of exogenous peptides to HLA-II restricted cells, primarily with afferent helper/inducer functions.

After corneal allograft, immune cells can recognise the nonself HLA antigens, leading to host immune system sensitivity, which results in an immune reaction and pathologic damage. Sensitisation of the host is largely due to donor antigen presenting cells carrying foreign HLA-II molecules and capable of activating host resting T cells. Activation of CD4+ helper T-cells leads to the activation and production of CD8+ cytotoxic T cells. These cells specifically attack donor cells bearing HLA-I and the sensitising antigen. This may therefore include epithelial, stromal, and endothelial cells.

  Prevention of Corneal Graft Rejection Top

Postoperative prophylactic immunosuppressive regimens can be devised according to the degree of risk of rejection. In low-risk cases, topical steroids (1% prednisolone acetate or 0.1% dexamethasone sodium phosphate) four times a day are adequate initially, and tapered-off in frequency and strength over a period of 4-6 months. Most surgeons give a subconjunctival injection of corticosteroids at the time of operation. Medium- and high-risk corneal allografts need to be more intensively treated and for a longer duration. For example, 1% prednisolone acetate or 0.1% dexamethasone sodium phosphate drops are given every two hours initially, with a corticosteroid ointment at night. The frequency and strength of the topical steroid is slowly reduced over a period of 6 months and a mild steroid, once daily, is maintained indefinitely.

Topical steroids are not always effective against graft rejection after high-risk corneal transplant. Besides, high dosage topical and long-term systemic corticosteroid treatments may induce severe complications. Thus, adjunctive treatments with local and systemic cyclosporine-A (CsA) have been suggested to prevent corneal graft rejection and improve the outcome in high-risk cases. CsA is a hydrophobic metabolite of the fungus Tolypocladium inflatum gans. It is a powerful immunomodulator that acts at the early stages of antigenic sensitisation. The mechanism of action is inhibition of proliferation of activated T lymphocytes, suppressing the generation of cytotoxic T lymphocytes while sparing T-suppressor cell subpopulations. Systemic CsA is greatly effective to reduce most organ allograft rejections and its beneficial effect has been proven also in corneal graft rejection.[23][24][25] Because of the potential side effects (most commonly hypertension, nephrotoxicity and hepatotoxicity) and cost of treatment,systemic CsA is usually reserved for high-risk corneal transplants and in those who have either bilateral disease or an affected single eye. In patients who have unilateral disease and a normal contralateral eye the indications for this treatment are less clear. The duration of CsA required to inhibit immune response is unknown. Theoretically, indefinite immunosuppression may be necessary to inhibit production of antigen-specific interleukin-2 and subsequent activation of T-lymphocytes. However, it has been suggested that the benefits of CsA in corneal transplantation may persist after the treatment is stopped. Most authors recommend the use of CsA for at least 6-12 months, and gradually tapered off.

Topical CsA has been used by several authors to prevent rejection in high-risk corneal transplants.[26],[27]

Alone or in combination with topical corticosteroids it may provide more specific control over the immune response with fewer side effects than corticosteroids or systemic CsA. It can be introduced in the postoperative period in cases of steroid-induced glaucoma, allowing a discontinuation of topical corticosteroids. Several aspects of topical treatment with CsA such as formulation of an effective vehicle (castor or olive oil), concentration (most commonly 2%), and frequency of use (usually four times daily) are still under investigation. Blood levels of CsA can be detected after topical administration but are usually low. In infants and small children receiving topical CsA the whole blood CsA level should be monitored periodically.[28]

Although corticosteroids and CsA have greatly reduced the rejection rate of corneal allografts, less toxic and more efficient methods of immunosuppression for corneal transplantation are still needed. FK-506, a new agent isolated from the fermentation broth of Streptomyces tsukubaensis, has been successfully used in organ transplantation and uveitis. This agent has immunosuppressive activities similar to and more potent than those of CsA. We have successsfully used this agent for the past three years in high-risk cases of corneal allograft rejection during the first 12 months after surgery. Side effects are similar to the ones induced by CsA and all patients undergo thoracic radiography, blood tests (renal function tests), urine tests, and blood pressure determination before and during FK-506 treatment. Topical FK-506 has been found beneficial in experimental models to prevent corneal graft rejection.

High-risk cases can benefit from other additional factors to reduce the incidence of graft rejection. Tissue matching in high-risk keratoplasty has been associated with a reduction of graft rejection. HLA and ABO gene products are expressed on all layers of the corneal tissue.[29][30][31][32][33] Several clinical studies indicate that HLA class I matching confers a survival advantage in high-risk cases,[34][35][36][37] although other authors did not support this observation.[5],[38],[39] We currently use HLA-I matched tissues in high-risk transplants. The clinical data on the relevance of HLA-DR and ABO blood group antigens in graft survival are even more ambiguous.[1],[5],[36][37][38][39][40][41][42]

An important practical approach would be to eliminate or reduce stromal vascularization before surgery [Figure:6]. Various modalities of treatment have been suggested for direct or indirect occlusion of corneal vessels. These include steroids, radiation, cystine, cryotheraphy, sulphuric acid, dextran, conjunctival recession, and laser treatment.[43][44][45][46 The use of 577 nm yellow dye laser appear to be the most effective modality of corneal vessel occlusion.[44],[46] The expense of the equipment and unavailability in most centres, particularly in the UK, prompted us to look for an alternative simple and inexpensive method of occluding corneal vessels. We are currently treating corneal vessels with fine needle diathermy before corneal grafting. Although our clinical impression is favourable, a controlled clinical trial is being conducted in our department to determine the long-term efficacy of this technique in reducing the risk of graft rejection in vascularised corneas.

  Treatment of Graft Rejection Top

Topical corticosteroids remain the mainstay of treatment of a rejection episode, although the optimum steroid dosage and route of administration is not established. For non-endothelial types of rejection we recommend 1% prednisolone acetate or 0.1% dexamethasone sodium phosphate drops 4-6 times a day for a week and tapered over a period of 6-8 weeks. For mild endothelial rejection the drops are given hourly during the waking hours with corticosteroid ointment at bedtime during two or three days, reducing them to two-hourly for 4-7 days. Initially, daily observation is recommended. Drops can be slowly tapered in 2-3 months. In severe endothelial rejection the drops are given hourly day and night for 48 hours. Then, drops are given hourly for two more days and then can be reduced to two hourly for 4-7 days. They should be slowly taperd for 3 months. Some authors recommend additional periocular adminsitration of corticosteroids.

Pulsed intravenous methylprednisolone and/or oral prednisolone have been used in cases of endothelial rejection. In the treatment of graft rejection, a single dose of methylprednisolone (500 mg), administered during the first week of the rejection episode, was associated with superior graft survival and less chance of a further rejection when compared with oral corticosteroids.[47],[48] Besides, the potential side effects of prolonged oral medication are avoided. The mechanism of pulse therapy is not known but it may inhibit the proliferating clones of immune cells, remove recirculating T lymphocytes from the blood, and suppress inflammation. We recommend pulse intravenous methylprednisolone in cases of endothelial rejection; we use a single dose in case of mild entothelial rejection and a three-day course in patients with severe endothelial rejection.

These regimens for reversing early graft rejection are usually effective. Inspite, it appears that in high-risk cases (i.e., vascularised corneas) rejection is more difficult to reverse. Adjunctive treatments with local and systemic CsA may be considered.[22][23][24][25][26][27] Other immunosuppressant agents such as FK-506 and azathioprine are rarely used during rejection episodes but can be a valid option in recalcitrant cases.[49],[50]

Lastly, patient education and awareness should be encouraged. There should be a clear communication with the patient to describe the symptoms of allograft rejection and to emphasise the importance of prompt evaluation and therapy.

  Future Directions Top

Several strategies may prove helpful to prevent or treat human corneal allograft antigens. Oral administration of antigens is an effective method to downregulate the immune response to alloantigens. Oral administration of corneal cells results in reduction of corneal allograft rejection in animal models.[51][52][53][54] Corneal allograft enhancement can also be achieved by oral immunisation with skin epidermal cells or spleen cells. Interestingly, orally induced graft enhancement is alloantigen specific. It is possible that local administration of corneal antigens may also include tolerance. Studies in a mouse model suggest that depletion of donor-derived Langerhans cells by ultraviolet radiation and hyperbaric oxygen can be used to improve corneal graft survival without jeopardising the functional integrity of the graft.[55] Monoclonal antibody therapy, which is frequently used in the treatment of solid organ graft rejection, is not used in corneal transplantation. Antibody therapy might be helpful to inhibit expansion and maturation of alloantigen specific T-lymphocytes. It may be feasible to administer monoclonal antibody locally. Another possible strategy is to aim adhesion molecules, which play an important role in immunological rejection after organ transplantation. Monoclonal antibodies against adhesion molecules suppress allograft rejection after penetrating keratoplasty in mice.[56]

Some serum factors may help to identify patients with highest risk of rejection or with early subclinical immune allograft reaction, who might benefit from more aggressive immunosuppression. Pleyer et al. suggested that elevation of serum tumour necrosis factor alpha can be found be in immunoreactive patients before the diagnosis of rejection is established by clinical criteria.[57]

  Acknowledgements Top

Thanks to Peter R. Laibson, for the illustrations included here, and to Vision Express for support to Dr. Azuara Blanco during his cornea and contact Lenses fellowship at Queen's Medical Centre from July 1997 - Dec. 1998.

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Clinical Features
Future Directions

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