The cornea is the transparent, dome-shaped front surface of the eye that focuses light onto the retina, enabling clear vision. When this tissue is damaged by disease, infection, or trauma, a corneal transplant (keratoplasty) replaces the diseased portion with healthy donor tissue. Although this procedure is common and successful, the recipient’s immune system may recognize the new tissue as foreign, leading to rejection. Understanding the mechanisms and observable signs of this immune response is the most effective way to protect the transplanted graft.
The Immune Mechanism Behind Rejection
The cornea possesses a natural defense mechanism called immune privilege, meaning it exists in an environment with reduced immune surveillance. This privilege is due to the cornea’s lack of direct blood vessels and lymphatic drainage, which typically serve as pathways for immune cells. This anatomical separation limits the immune system’s exposure to the donor’s unique surface proteins, known as alloantigens.
However, immune privilege is not absolute and can be broken down, particularly if the recipient’s eye has pre-existing inflammation or corneal neovascularization (the growth of new blood vessels). When the immune system detects the foreign alloantigens, specialized antigen-presenting cells (APCs) become activated. These cells migrate from the cornea to regional lymph nodes, initiating a systemic immune response by activating T-lymphocytes.
The activated T-cells then travel back to the eye to attack the donor cornea, which is the physical manifestation of rejection. Rejection can affect different layers, including the epithelium, stroma, and endothelium. Endothelial rejection is the most damaging because the endothelial layer, which pumps fluid out of the cornea to maintain clarity, cannot regenerate. Damage to these cells leads to permanent swelling and clouding of the graft.
Recognizing the Warning Signs of Rejection
The signs of corneal graft rejection can often be remembered using the mnemonic RSVP: Redness, Sensitivity to light, Vision decrease, and Pain. A sudden or gradual change in vision, making the world appear hazy or cloudy, is often the first symptom noticed. This reduction in visual acuity is caused by corneal edema, the accumulation of fluid in the graft tissue.
The physical signs visible to a clinician are more specific and involve detecting inflammatory cells. Keratic precipitates (KPs) are white blood cells adhered to the back surface of the donor cornea (the endothelium). KPs can appear as scattered, fine dots or as larger, aggregated clumps of immune cells.
A specific sign of endothelial rejection is the Khodadoust line, named after the ophthalmologist who described it. This is a linear collection of inflammatory cells, primarily lymphocytes, moving across the graft’s endothelial surface. The area the line has passed over becomes swollen and opaque, while the area immediately in front of the advancing line remains clear. Recognizing these signs early is paramount, as prompt intervention increases the chance of reversing the rejection episode before permanent graft failure occurs.
Treatment Options for Acute Rejection
The immediate response to an acute rejection episode is the administration of high-dose topical corticosteroids. These anti-inflammatory eye drops are the gold standard treatment, rapidly suppressing the localized immune response within the eye. A typical protocol involves administering a highly concentrated steroid, such as prednisolone acetate 1%, as frequently as every one to two hours while the patient is awake.
The initial aggressive dosing is sustained for several days until inflammation subsides, after which the frequency is gradually tapered. The goal of this intensive therapy is to overwhelm the immune cells and halt their attack on the donor endothelial cells. If the rejection is severe, or if the initial topical treatment is not effective within 24 to 48 hours, additional measures may be necessary.
These escalated treatments can include the temporary addition of oral immunosuppressants, such as prednisone, to provide stronger systemic suppression. In rare, severe, or unresponsive cases, the ophthalmologist may consider subconjunctival or intravenous steroid injections to deliver a high concentration of medication directly to the site of inflammation. Successful treatment is defined by the reversal of corneal edema and the restoration of graft clarity before inflammation causes irreversible loss of the endothelial cells.
Long-Term Graft Survival and Prevention
Even after a successful reversal of an acute rejection episode, the transplanted cornea remains at risk for the rest of the patient’s life, with rejection reported decades after the procedure. Consequently, long-term maintenance therapy and diligent follow-up care are necessary to ensure graft survival. Most patients remain on a low-dose maintenance regimen of steroid eye drops indefinitely to keep the immune system suppressed at the ocular surface.
Certain factors increase the risk of future rejection, including corneal neovascularization and a history of previous graft failure. Inflammation from other eye conditions, such as glaucoma or pre-existing eye surface diseases, also raises the likelihood of an immune reaction. Patients must adhere strictly to the prescribed medication schedule and attend regular eye examinations, as the long-term prognosis is directly tied to the ability to detect and manage these risks.
If a rejection episode is successfully reversed, the graft can function well for many years, but the long-term survival rate is lower than for grafts that have never experienced rejection. Conversely, if rejection is not caught and treated quickly, permanent loss of endothelial cells causes the cornea to swell and become permanently cloudy, resulting in graft failure and the need for a repeat transplant. The need for lifetime surveillance is a trade-off for restoring vision through transplantation.