Corneal Graft Rejection

Despite the cornea’s special protection from the immune system, corneal graft rejection remains the most common cause of transplant failure, with the body’s immune response targeting the donor tissue and threatening the clarity of vision that the transplant was meant to restore.

Table of contents

• What is Corneal Graft Rejection?
• Understanding the Cornea’s Immune Privilege
• Success Rates and Risk Factors
• What Causes Rejection
• Signs and Symptoms
• Types of Rejection
• Treatment Options
• Outlook and Recovery

What is Corneal Graft Rejection?

Corneal graft rejection is a specific immune response where the body recognizes the transplanted cornea as foreign tissue and attacks it^[1]. The cornea is the clear, dome-shaped front surface of your eye that allows light to enter. When the cornea becomes damaged or diseased, doctors may replace it with healthy tissue from a donor through a procedure called corneal transplantation or keratoplasty^[4].

It is important to understand the difference between rejection and failure. Graft rejection specifically refers to the immune system’s attack on the donor tissue. Graft failure, on the other hand, describes any reason the transplant stops working and becomes cloudy, which could be due to rejection, infection, or other causes^[13]. Rejection leads to failure, but failure is not always caused by rejection.

Although the first successful corneal transplant was performed in 1906, it took another fifty years before doctors first described a previously clear graft becoming cloudy. A French doctor named Paufique called this “disease of the graft” and suggested that the donor tissue was being attacked by the recipient’s immune system^[1].

Understanding the Cornea’s Immune Privilege

The cornea has special characteristics that help protect it from immune system attacks. Both the corneal bed (where the transplant sits) and the anterior chamber (the fluid-filled space at the front of the eye) are called “immune-privileged sites”^[1]. This means they have natural defenses against immune responses.

The cornea’s immune privilege comes from several features. It has no blood vessels, which limits the access of immune cells that could attack foreign tissue. There are also no associated lymphatic vessels or lymph nodes, so the opportunity for the immune system to recognize and respond to foreign tissue is reduced. Additionally, the cornea expresses immune markers to a lesser extent than other body tissues^[2].

However, this protection can be compromised by prolonged inflammation, extensive development of blood vessels in the cornea, and other factors, which then increases the risk of rejection^[2].

Success Rates and Risk Factors

Despite the cornea’s immune privilege, rejection remains the most common cause of corneal graft failure. For first-time transplant recipients who have no blood vessels growing into their corneal bed, the two-year success rate exceeds 90%. However, this drops dramatically to 35% to 70% in recipients who have high-risk factors for rejection^[1].

In the United States, approximately 80,000 corneal transplants were performed in 2021^[2]. Large studies show that 18% to 21% of people receiving a corneal transplant experience some form of rejection after the procedure^[6]. In one study, 23% of patients had at least one rejection episode within five years, and 37% of those who experienced rejection went on to have graft failure^[2].

One-third of all corneal graft failures show signs of destructive attack by the immune system. A rejection episode results in a loss of donor endothelial cells, which are critical for maintaining corneal transparency^[1]. Because human endothelial cells cannot repair themselves through cell division, the loss of these cells is permanent. When the number of endothelial cells falls below the minimum needed to prevent swelling in the cornea, clarity is lost and vision becomes impaired^[1].

Research shows that following a rejection episode, graft failure is likely to occur in up to one-third of cases within six months^[13].

What Causes Rejection

Certain conditions in the eye receiving the donor graft indicate a higher risk of rejection. High-risk situations include eyes with many blood vessels growing into the cornea, or eyes that have previously rejected a graft and remain inflamed at the time of transplantation^[6].

Other factors that may increase risk include transplants in children, using large-sized donor corneas, or positioning the donor cornea very close to the edge of the recipient’s cornea. A patient may have more than one of these high-risk factors^[6].

Patients may also have other eye problems such as glaucoma or issues with the eye surface that could lead to a higher chance of rejection. After the transplant is completed, problems such as blood vessel growth on the recipient’s cornea or graft wound, loosened sutures, or graft infections can trigger rejection^[6].

Signs and Symptoms

Graft rejection is characterized by one or more of these patient symptoms: redness, pain, sensitivity to light (photophobia), and decreased vision^[13]. These symptoms should be taken seriously, as early recognition is key to preserving the transplant.

Common clinical findings that doctors look for include corneal swelling (edema), infiltration of cells into the cornea, reaction in the anterior chamber of the eye, deposits on the back surface of the cornea called keratic precipitates, and redness around the edge of the cornea^[13].

One finding that clearly indicates rejection is called a rejection line. This can appear on either the outer surface (epithelial) or inner surface (endothelial, also called a Khodadoust line) of the cornea^[13].

Types of Rejection

There are different types of corneal graft rejection, depending on which layer of the cornea is affected.

Epithelial rejection occurs at the outer edge of the graft and is associated with enlarged blood vessels in the area and an elevated line on the surface that stains with fluorescein dye^[13].

Subepithelial or chronic stromal rejection involves whitish deposits that look similar to those found in viral eye infections. This type can be confused with viral conjunctivitis, so doctors should consider rejection until proven otherwise^[13].

Endothelial rejection is the most common form, occurring in up to 50% of rejection cases. It affects the inner layer of the cornea and is associated with blood vessel enlargement around the cornea, graft swelling, reaction in the front chamber of the eye, deposits on the inner corneal surface, and a Khodadoust line. A Khodadoust line appears as segments of corneal swelling and white blood cells on the inner surface next to areas of clear cornea, forming a distinct line^[13].

Epithelial or stromal rejection without involvement of the endothelial layer usually does not progress to graft failure. However, these types should still be treated aggressively because they indicate the immune system has recognized the graft and may lead to more severe endothelial rejection^[7].

Treatment Options

Treatment of graft rejection depends on the type of rejection, but in all cases, corticosteroids (anti-inflammatory medications) applied directly to the eye are the main treatment^[7].

For epithelial and stromal rejection, topical corticosteroids such as dexamethasone 0.1% or prednisolone acetate 1% are prescribed four to six times a day until signs of rejection resolve, followed by a slow reduction in frequency. Patients should be followed closely to ensure the rejection is improving and that endothelial rejection has not developed^[7].

In cases of endothelial rejection, treatment must be more aggressive. Topical corticosteroids should be used every hour while awake and as frequently as possible at night for two to three days, followed by every two hours while awake. Higher potency topical steroids may also be considered. Steroid ointment may be used at bedtime. Treatment should continue until signs of rejection resolve, with medications tapered slowly over several weeks to months depending on response^[7].

Therapy should be continued for at least four weeks without a response before determining that the graft has failed^[7].

For more severe endothelial rejections, recurrent rejections, or high-risk patients, other routes of steroid administration can be used. Corticosteroids may be given by injection under the conjunctiva (the membrane covering the white of the eye), or through a collagen shield soaked in corticosteroids that is applied to the cornea^[7].

In severe or high-risk cases, systemic steroids or immunosuppressants (medications that suppress the immune system) may be used. Oral prednisone is generally started at dosages of 60-80 mg daily and continued for as long as one to two weeks before gradually reducing the dose. Pulsed steroids (a single intravenous administration of 500 mg methylprednisolone) have been shown to improve graft survival compared with oral steroids, especially in patients who present early in a rejection episode. Pulsed steroids also reduce the risk for future rejection episodes^[7].

In all cases of rejection, eye pressure should be monitored because steroids can increase pressure inside the eye^[7].

Outlook and Recovery

While most corneal transplant operations are successful, they carry a small risk of complications, including rejection of the donor cornea^[4]. The earlier rejection is detected and treated, the better the chances of saving the graft.

Understanding the hurdles that were overcome while obtaining the donor tissue should make any process that threatens the graft urgent and important for both patients and doctors. Any patient who has had a corneal transplant and experiences decreased vision, redness, or other symptoms should seek medical attention promptly^[13].

While reversing acute graft rejection episodes is generally more successful in the cornea compared to other transplanted organs, effective prevention strategies for high-risk corneal transplant recipients remain a challenge. For this reason, the impact of graft rejection continues to be an important focus in corneal research^[1].