Understanding Corneal Graft Rejection

When someone receives a cornea transplant, they are receiving tissue from another person, known as a donor. The cornea is the clear, dome-shaped surface at the front of the eye that allows light to enter. Although both the corneal bed where the transplant is placed and the area inside the eye called the anterior chamber (the space behind the cornea and in front of the iris) are considered immune-privileged sites—meaning they normally have some protection from immune system attacks—rejection can still happen.^[1]

Despite this natural protection, the most common cause of corneal graft failure across all studies is allogeneic rejection, which means the recipient’s immune system recognizes the donor tissue as foreign and launches an attack against it. This rejection process leads to the loss of special cells called endothelial cells, which are critical for keeping the cornea transparent and clear. These cells act like tiny pumps that prevent the cornea from swelling with fluid.^[1]

What makes endothelial cells particularly vulnerable is that human endothelial cells do not repair themselves through cell division. Once they are lost, they cannot be replaced. When the number of these cells drops below a certain threshold, the cornea can no longer prevent fluid buildup, leading to swelling and cloudiness that blocks vision.^[1]

How Common Is Corneal Graft Rejection?

Corneal transplantation has become increasingly common over the decades. In 2021, approximately 80,000 corneal transplantations were performed in the United States alone.^[2] Rejection is the most common cause of graft failure in the late period after surgery, meaning months or years after the initial transplant procedure.^[2]

The likelihood of rejection varies widely depending on several factors. For first-time graft recipients who have no blood vessels growing into their corneal bed before surgery, the outlook is quite good. In these low-risk cases, two-year survival rates exceed ninety percent. However, when recipients have high-risk factors such as blood vessels in the cornea or previous graft rejection, the success rate drops significantly to between thirty-five and seventy percent.^[1]

Large studies show that between eighteen and twenty-one percent of people who receive a corneal graft experience some form of rejection after the transplant.^[6] One study found that at the five-year follow-up point, twenty-three percent of subjects had experienced at least one rejection episode, and of those who experienced rejection, thirty-seven percent went on to have graft failure.^[2]

Different types of corneal transplant procedures carry different rejection risks. Full-thickness transplants, known as penetrating keratoplasty, have rejection rates reported between fourteen and thirty-three percent in various studies. Partial thickness transplants, such as deep anterior lamellar keratoplasty and newer procedures like Descemet stripping endothelial keratoplasty, generally have lower rejection rates, ranging from six to twenty percent.^[2]

What Causes Corneal Graft Rejection

Corneal graft rejection happens when the recipient’s immune system recognizes the donor corneal tissue as foreign. The immune system normally protects the body by attacking invaders like bacteria and viruses, but in transplantation, it can mistakenly identify the new tissue as something harmful that needs to be destroyed.^[13]

The cornea has certain features that usually help protect it from immune attack. It lacks blood vessels and lymphatic vessels, which limits the access of immune cells like lymphocytes to the tissue. The cornea also expresses fewer MHC antigens (proteins that the immune system uses to identify “self” versus “foreign”) compared to other tissues. However, these protective features can be compromised by prolonged inflammation or extensive blood vessel growth into the cornea.^[2]

The historical understanding of corneal graft rejection began in the mid-twentieth century. Although the first successful corneal graft was performed in 1906, it took another fifty years before doctors first described the clouding of a previously clear graft. A doctor named Paufique called this “maladie du greffon,” or disease of the graft, and suggested it was caused by the recipient’s immune system becoming sensitized to the donor tissue.^[1]

Risk Factors for Rejection

Several conditions present before surgery can indicate a higher risk of graft rejection and failure. The most significant high-risk factor is the presence of blood vessels growing into the corneal bed where the graft will be placed. When blood vessels are present, they provide a highway for immune cells to reach and attack the donor tissue. Eyes that have previously rejected a graft and remain inflamed at the time of a new transplantation are also at very high risk.^[6]

Other factors that may increase rejection risk, though the evidence is not as strong, include receiving a graft during childhood, using large-sized donor corneas, or placing the donor cornea very close to the edge of the recipient’s cornea. Some patients may have multiple high-risk factors at the same time. Additionally, other eye problems like glaucoma or issues with the surface of the eye can increase the chance of rejection.^[6]

After a successful transplant, certain complications that develop can trigger rejection. These include the growth of new blood vessels into either the recipient’s cornea or the graft wound, loosened or broken sutures, and infections of the graft. Careful monitoring and management of these post-surgical complications are essential to prevent rejection episodes.^[6]

Symptoms of Corneal Graft Rejection

Patients experiencing graft rejection typically notice one or more warning symptoms. The most common complaint is decreased or blurry vision, which happens because the rejecting graft becomes swollen and cloudy. Many patients also experience redness of the eye, particularly around the colored part of the eye. Pain or discomfort in the eye is another frequent symptom, along with increased sensitivity to light, called photophobia.^[13]

During an examination by an eye doctor, several clinical signs may indicate rejection is happening. These include swelling of the corneal graft, folds in a layer of the cornea called Descemet’s membrane, inflammation inside the anterior chamber, and small deposits on the back surface of the cornea known as keratic precipitates. One particularly characteristic finding is called a rejection line, which appears as a distinct line across the cornea where immune cells are attacking the tissue.^[13]

There are different types of rejection that affect different layers of the cornea. Epithelial rejection affects the outermost layer and appears at the edge of the graft with engorged blood vessels and an elevated ridge that can be seen with special staining. Stromal rejection affects the middle layer and may show white infiltrates similar to those seen in viral eye infections. Endothelial rejection is the most common type, occurring in up to fifty percent of rejection cases, and affects the critical inner layer of cells that keep the cornea clear.^[13]

Prevention Strategies

Preventing corneal graft rejection begins with careful evaluation before surgery. Doctors assess risk factors and work to optimize conditions for transplant success. For patients identified as high-risk, special preventive measures may be taken, though effective prevention strategies for these patients remain less well-established compared to treatment of acute rejection episodes.^[1]

After surgery, the main prevention strategy involves the long-term use of medications to suppress the immune system. Topical corticosteroid eye drops, such as prednisolone acetate or dexamethasone, are the mainstay of preventive therapy. These medications help dampen the immune response that could lead to rejection. The dosage and frequency are typically higher in the first months after surgery and then gradually reduced, but some patients may need to continue using low doses indefinitely.^[7]

For high-risk patients, additional preventive medications may be used. Some patients benefit from topical cyclosporine, a powerful immunosuppressant that can be applied directly to the eye. In very high-risk cases, doctors may prescribe systemic immunosuppressive medications taken by mouth, such as oral cyclosporine, azathioprine, or oral corticosteroids. These systemic medications come with more potential side effects and require careful monitoring, but they may be necessary for patients with multiple previous graft failures or severe risk factors.^[11]

Avoiding complications after surgery is another important prevention strategy. This includes protecting the eye from injury, treating any infections promptly, managing conditions like glaucoma that can stress the graft, and keeping the eye’s surface healthy. Patients should attend all follow-up appointments so their doctor can monitor the graft’s health and detect early warning signs of rejection.^[6]

Some patients may be candidates for newer surgical techniques that reduce rejection risk. Partial thickness transplants, which replace only the diseased layers of the cornea rather than the full thickness, generally have lower rejection rates. Researchers are also exploring novel approaches, such as treating donor corneas with special molecules before transplantation to make them more likely to be accepted by the recipient’s immune system.^[18]

How the Body Reacts: Understanding the Process

When rejection occurs, the body’s immune system goes through a complex process of recognizing and attacking the donor tissue. The immune privilege of the cornea works through several mechanisms. The lack of blood vessels means immune cells have limited access to the tissue. The absence of lymphatic vessels and lymph nodes reduces the opportunity for foreign antigens from the donor to be presented to T cells, which are key immune cells that coordinate attacks on foreign tissue.^[2]

However, when conditions compromise this immune privilege—such as inflammation, blood vessel growth, or previous immune sensitization—the protective barriers break down. Immune cells can then enter the graft, recognize donor antigens as foreign, and launch an attack. This immune response primarily targets the endothelial cells on the inner surface of the cornea.^[8]

The destruction of endothelial cells has serious consequences because these cells cannot regenerate. Their job is to pump excess fluid out of the cornea, maintaining its clarity. When enough endothelial cells are lost, the pumping function fails, fluid accumulates in the corneal tissue, and the cornea swells and becomes cloudy. This process is called endothelial decompensation, and it results in vision loss.^[1]

The timing of rejection varies. Some rejection episodes occur within the first year after transplantation, while others may happen many years later. The risk never completely disappears, which is why long-term monitoring and preventive medication use remain important throughout a patient’s life after transplant.^[8]