Corneal Allograft Rejection and Failure

Key points of this disease

• Rejection after corneal transplantation is a delayed-type hypersensitivity reaction to the allogeneic donor cornea and is a major cause of penetrating keratoplasty (PKP) failure.
• In PKP, rejection occurs in 10–30% of cases postoperatively, with more than half occurring within the first year, but late-onset cases also exist. Rejection, glaucoma, and infection are the three major complications of corneal transplantation.
• Rejection is classified into three types: epithelial, stromal, and endothelial. Endothelial rejection has the greatest impact on graft survival.
• Endothelial rejection is characterized by localized keratic precipitates (KP) on the graft and the Khodadoust line.
• Treatment is primarily frequent topical steroids. For endothelial rejection, subconjunctival injection and mini-pulse therapy (methylprednisolone 250 mg IV for 3 days) are added.
• In high-risk eyes such as those with corneal neovascularization involving two or more quadrants, regrafts, or age ≤40 years, systemic cyclosporine or tacrolimus is used.
• Descemet membrane endothelial keratoplasty (DMEK) has the lowest antigen load, with an average rejection rate of 1.9% (range 0–5.9%).

1. Corneal Allograft Rejection and Failure

Corneal transplantation is one of the most successful organ transplants. For first-time penetrating keratoplasty (PKP) in low-risk eyes, the 5-year survival rate reaches 95%. This high success rate is supported by the immune privilege of the cornea.

Factors contributing to corneal immune privilege include:

• Lack of blood vessels, creating a barrier to immune component delivery
• Lack of lymphatics, limiting antigen presentation
• Expression of Fas ligand, inducing apoptosis of activated T cells
• Very low expression of MHC antigens
• Anterior chamber-associated immune deviation (ACAID): systemic immune tolerance is induced to antigens in the anterior chamber

However, in high-risk eyes with corneal neovascularization, the failure rate at 3 years can exceed 35%. Even under immune privilege, the most common cause of graft failure is irreversible immunological rejection ¹⁾.

Definition and Distinction

“Graft rejection” refers to the host’s specific immune response against the donor cornea. Primary graft failure is a condition in which the graft does not become clear within 8 weeks after surgery due to defects in the donor tissue itself, surgical trauma, or improper preservation, and is not immune-mediated ³⁾. It occurs in about 0.1% of PKP cases.

The diagnosis of rejection is made only for grafts that have maintained clarity for at least 2 weeks after surgery. More than half of the cases occur within the first year after surgery, with a peak between 6 months and 1 year. However, it can also occur more than 20 years after surgery. The rate of progression from rejection to failure is reported to be approximately 49%.

Corneal transplantation is the most frequently performed tissue transplant worldwide. According to an international survey in 2012, PKP accounted for about 70% of all corneal transplants ¹⁾. In recent years, DSAEK and DMEK for endothelial diseases have rapidly become widespread, and DALK for keratoconus and post-keratitis scars has become a standard option, significantly changing the composition of surgical procedures. However, PKP remains essential for extensive corneal opacities and deformities and carries the highest risk of rejection ¹⁾.

Penetrating Keratoplasty (PKP)

Rejection rate: Approximately 4.9–28.9% ⁷⁾

Main cause of failure: Rejection (early) + endothelial failure (late) ³⁾

Characteristics: Highest antigenicity due to inclusion of full-thickness donor tissue

Deep Anterior Lamellar Keratoplasty (DALK)

Rejection rate: 1–24% ⁴⁾

Advantage: Eliminates the risk of endothelial rejection

Challenge: Stromal rejection can still occur ⁴⁾

Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK)

Rejection rate: Average 10% (range 0–45%)

Primary failure rate: Average 5% (range 0–29%)

Features: Some reports indicate no significant difference compared to PKP³⁾

Descemet Membrane Endothelial Keratoplasty (DMEK)

Rejection rate: Average 1.9% (range 0–5.9%)⁷⁾

Primary failure rate: 1.7%

Features: Lowest antigenicity and low rejection rate³⁾

Large cohort studies have shown that DMEK has a significantly lower risk of rejection compared to PKP and DSAEK³⁾. A meta-analysis comparing UT-DSAEK and DMEK found no significant difference in rejection risk at 12 months postoperatively²⁾. In a Dutch multicenter randomized controlled trial of 54 eyes, the DMEK group had a significantly higher rate of achieving 20/25 or better vision at 12 months compared to the DSAEK group (66% vs 33%, P=0.02), while there were no significant differences in endothelial cell density or refractive changes¹¹⁾.

Q When is corneal transplant rejection most likely to occur?

A

More than half of cases occur within the first year after surgery, especially between 6 months and 1 year. However, rejection can also occur long after surgery, so if symptoms such as redness, blurred vision, or decreased vision appear even years later, prompt medical attention is necessary. There have been reports of rejection triggered by vaccination more than 20 years after surgery¹⁰⁾.

Q How different are the rejection rates between PKP and DMEK?

A

The rejection rate for PKP is approximately 4.9–28.9%, whereas for DMEK it is significantly lower at an average of 1.9% (range 0–5.9%). This difference is mainly due to the amount of donor tissue transplanted. PKP transplants epithelium and stroma containing dendritic cells, resulting in higher antigenicity. In contrast, DMEK transplants only Descemet’s membrane and endothelium, which has lower antigenicity and does not require sutures, reducing the risk. However, reports indicate that about 6% of DMEK cases experience rejection after discontinuation of steroids, highlighting the importance of long-term steroid use.

2. Main Symptoms and Clinical Findings

Slit-lamp microscopy image of a transplanted cornea with rejection

Zheng Y, et al. Clinicopathological correlation analysis of (lymph) angiogenesis and corneal graft rejection. Mol Vis. 2011. Figure 1. PMCID: PMC3130724. License: CC BY.

Findings of corneas with mild edema and neovascularization due to rejection (A, B), and corneas with severe neovascularization and perforation (C, D). These correspond to corneal opacity discussed in section “2. Main Symptoms and Clinical Findings.”

Subjective Symptoms

Patients present with blurred vision, conjunctival injection, eye pain, foreign body sensation, and decreased visual acuity. There are peaks of onset at 3 months and 1 year after surgery. If subjective symptoms appear, prompt medical attention is necessary.

Clinical Findings

The diagnostic criteria for rejection include any of the following: conjunctival injection, photophobia, decreased visual acuity, anterior chamber cells, keratic precipitates (KP), endothelial or epithelial rejection lines, subepithelial infiltrates, and localized graft edema¹⁾.

Graft-localized KP are characteristic, and KP on the recipient cornea are not observed. The Khodadoust line is a linear deposit on the corneal endothelium and represents the advancing front of endothelial rejection.

Types of Rejection

Rejection is classified into three types based on the layer affected: epithelial, stromal, and endothelial. Endothelial rejection has the greatest impact on graft prognosis, and delay in treatment leads to irreversible endothelial failure and vision loss.

Rejection Type	Frequency	Main Findings
Epithelial	Approximately 2%	Linear ridge migrating from the limbus (epithelial rejection line)
Stromal	—	Stromal edema is the only finding
Endothelial type	Approximately 50%	KP, Khodadoust line, edema

Epithelial rejection has a low frequency of about 2% of all rejection episodes. As a precursor lesion, round subepithelial infiltrates of 0.2–0.5 mm are observed just below Bowman’s membrane. As it progresses, an edematous raised linear lesion (epithelial rejection line) forms. It has little effect on the clear healing of the graft itself, but can trigger endothelial rejection.

Stromal rejection has stromal edema as the only finding. In DALK, stromal infiltration and interface neovascularization may be seen as stromal immune rejection ⁴⁾. It is difficult to differentiate from corneal edema due to endothelial rejection in PKP eyes.

Endothelial rejection accounts for about 50% of all rejection episodes and is clinically the most important. Localized corneal endothelial deposits within the graft are a key finding, and when a Khodadoust line forms, it is accompanied by stromal edema at the same site. Mixed type (epithelial + endothelial, etc.) is seen in about 30%.

Q What is Khodadoust line?

A

Khodadoust line is a linear corneal endothelial deposit characteristic of endothelial rejection. It represents the advancing front of rejection that progressively moves across the graft endothelium; in the area where the line has passed, endothelial cells are damaged, causing stromal edema. If Khodadoust line is observed, prompt and intensive steroid treatment is necessary.

Differential diagnosis of KP

Finding	Rejection	HSV/VZV endotheliitis	CMV endotheliitis
Distribution of KP	Localized within the graft	Also attached outside the graft	Also attached outside the graft
Color of KP	White to gray-white	Brown	Brown to white
Characteristic findings	Khodadoust line	Arlt’s triangle	Coin lesion

Rejection is characterized by KP localized to the graft, whereas viral endotheliitis is differentiated by the presence of KP also outside the graft. Since corneal endothelial deposits may sometimes be donor-derived at the time of corneal transplantation, recording the distribution of KP during daily examinations is useful for differentiation.

3. Causes and Risk Factors

Risk Factors for Penetrating Keratoplasty

Cases in which PKP is prone to rejection are called high-risk eyes, and the following factors are listed.

• Vascular invasion into the corneal stroma in two or more quadrants: The most established risk factor.
• Preoperative inflammation: Inflammatory corneal disease after ocular surface disease or infectious keratitis
• Corneal neovascularization (two or more quadrants)
• Young recipient (≤40 years): Younger age is associated with more active immune response
• Large graft: Increases the amount of transplanted antigen and proximity to limbal vessels
• Previous graft or rejection history: Prior sensitization increases rejection rate
• Suture loosening or breakage: Exposed sutures induce neovascularization and immune response
• History of glaucoma or glaucoma surgery
• Anterior synechiae: Contact between iris and donor endothelium triggers immune response
• Atopic predisposition: Th2-dominant immune background may contribute to rejection

Risk factors for endothelial keratoplasty/Descemet membrane endothelial keratoplasty

• Pre-existing glaucoma
• Steroid-responsive intraocular pressure elevation
• Association with herpes infection

In DMEK, rejection may be triggered during steroid tapering. In one case, rejection occurred 15 months after DMEK when switching from betamethasone to fluorometholone⁷⁾. Peripheral anterior synechiae (PAS) have also been reported as a risk factor for DMEK rejection⁷⁾.

Impact of HLA matching

While the benefit of HLA matching is clear in organ transplantation, results are inconsistent in corneal transplantation¹⁾. The Corneal Transplant Follow-up Study II (CTFS II) conducted in the UK was a large prospective clinical trial examining the impact of HLA class II (HLA-DR) matching in high-risk PKP¹⁾. From 1998 to 2011, 1133 transplants were collected and stratified into 0, 1, or 2 HLA-DR mismatches under the condition of ≤2 HLA class I mismatches¹⁾. DNA-based methods (PCR-SSP/PCR-SSO) were used for donor and recipient tissue typing to avoid errors from serological techniques¹⁾.

In CTFS II, no clear relationship was found between the number of HLA-DR mismatches and the incidence of rejection¹⁾. As shown in rodent models, corneal graft rejection involves multiple distinct immune pathways, and this redundancy of immune responses is thought to partly explain the inconsistent results of HLA matching studies¹⁾.

Vaccination-Related Rejection

Multiple cases of corneal transplant rejection after COVID-19 vaccination have been reported. It can occur with mRNA vaccines (BNT162b2), viral vector vaccines (ChAdOx1), and inactivated vaccines (Sinopharm).

Two cases of acute PKP rejection were reported 2 weeks after the first dose of BNT162b2 vaccine⁶⁾. Neither had a history of previous rejection, and both responded well to topical and systemic steroids⁶⁾.

A case of endothelial rejection after femtosecond laser corneal transplantation occurred 2 weeks after ChAdOx1 vaccination⁸⁾. Khodadoust line and anterior chamber inflammation were observed, and recovery occurred after 5 weeks of steroid treatment⁸⁾.

Two cases of rejection after Sinopharm inactivated vaccine have also been reported⁹⁾. A literature review has accumulated at least 20 cases of vaccine-related rejection, with the majority recovering with steroid treatment⁹⁾.

There is a case of rejection occurring 10 days after BNT162b2 vaccination in a PKP that had been stable for over 20 years post-surgery¹⁰⁾.

Although causality is not established, a hypothesis has been proposed that vaccination may trigger rejection through induction of MHC class II antigen-presenting cells⁹⁾.

Q Can corneal transplant rejection occur after COVID-19 vaccination?

A

Corneal transplant rejection after COVID-19 vaccination has been reported with mRNA, vector, and inactivated vaccines. It often occurs 1 to 3 weeks after vaccination, and most cases respond to steroid treatment. Meta-analyses have ruled out vaccine-induced rejection in solid organ transplants, but case accumulation is ongoing for corneal transplants. Since causality is not established, it is recommended that corneal transplant patients increase steroid use before vaccination and seek early medical attention after vaccination.

Prevention and Daily Care

When corneal transplant patients receive vaccination, it is recommended to increase or add steroid eye drops starting 3 days to 1 week before vaccination, and to self-monitor for changes in vision, redness, or eye pain after vaccination. For patients with a history of herpetic keratitis, prophylactic antiviral therapy should be considered. Early detection of rejection greatly affects graft prognosis, so it is important to seek medical attention without waiting until the next day if any abnormalities are noticed.

4. Diagnosis and Examination Methods

Slit-Lamp Microscopy

Check for graft-localized KP, Khodadoust line, corneal edema, and anterior chamber cells. Epithelial rejection lines start near congested limbal vessels and move across the graft border.

Auxiliary Examinations

• Corneal pachymetry: Measurement of corneal thickness is useful for evaluating endothelial function, and especially if preoperative baseline data are available, it helps in early detection of rejection ³⁾.
• Anterior segment OCT: Evaluates the adhesion between the graft and host cornea, distribution of stromal edema, and poor adhesion of DSAEK grafts.
• Specular microscopy: Quantitatively evaluates corneal endothelial cell density. The minimum endothelial cell density for donor corneas is set at 2200 cells/mm² by CTFS II ¹⁾.
• Anterior chamber PCR testing: Performed when differentiation from herpes virus or CMV infection is difficult ⁷⁾.
• Fluorescein angiography (FA): May be used to evaluate graft vascularization and activity of new vessels.
• Confocal microscopy: Allows evaluation of dendritic cell infiltration and inflammatory cells in the cornea, and its use is expanding in research.

Differential Diagnosis

The main conditions requiring differentiation from endothelial rejection are as follows.

• Herpetic keratouveitis: Extremely difficult to differentiate from endothelial rejection. The only distinguishing point is the pattern of keratic precipitates (KP); in herpes, they attach not only to the graft but also to the surrounding recipient cornea.
• CMV corneal endotheliitis: Characterized by coin lesion-like KP and chronic persistent intraocular pressure elevation. Anterior chamber PCR is useful for confirmation ⁷⁾.
• Graft endothelial dysfunction: Endothelial cell density gradually decreases without rejection, leading to dysfunction over time. Differentiation is based on the presence or absence of a history of inflammation.
• Postoperative infection: It is necessary to rule out bacterial, fungal, and herpes virus infections before intensifying immunosuppression. Exposed suture sites are particularly prone to infection.
• Steroid-responsive ocular hypertension: If intraocular pressure rises during long-term steroid use, differentiation from steroid-induced glaucoma is necessary.

Q How do you differentiate rejection from herpetic corneal endotheliitis?

A

In rejection, KP is confined to the graft, and intraocular pressure elevation is rare. In HSV/VZV endotheliitis, KP also attaches outside the graft and is accompanied by acute intraocular pressure elevation. In CMV endotheliitis, coin lesion-like KP and chronic persistent intraocular pressure elevation are characteristic. If confirmation is difficult, anterior chamber PCR, serum antibody tests, and response to steroids are comprehensively evaluated.

5. Standard Treatment

Treatment Protocol for Acute Rejection

The basic treatment for rejection is anti-inflammatory therapy with steroids.

Mild (epithelial/stromal type)

• Start with Rinderon PF Otic/Ophthalmic Solution 0.1% (betamethasone sodium phosphate, preservative-free) applied 6 to 8 times daily.
• Taper over 6 to 8 weeks.

Severe (endothelial type, Khodadoust line positive)

• Apply Rinderon PF Otic/Ophthalmic Solution 0.1% every hour.
• If necessary, administer Solu-Medrol Injection (methylprednisolone sodium succinate) 250 mg/day intravenously for 3 days (mini-pulse therapy).
• Dexamethasone or betamethasone may also be injected subconjunctivally.
• After remission, continue betamethasone 0.1% four times daily for at least one year, then switch to a lower concentration steroid for long-term maintenance. Continued steroid use is thought to help suppress recurrence of rejection ³⁾.

With early treatment, more than 50% of acute rejection episodes recover; however, delayed treatment can lead to irreversible endothelial cell loss and graft failure. Patient education is important: patients should be aware of postoperative symptoms (redness, blurred vision, eye pain, photophobia) and seek early medical attention if any changes occur.

Postoperative Preventive Management

For prevention of rejection after corneal transplantation, a two-step protocol based on risk stratification is used.

Postoperative Management for Normal-Risk Eyes

Steroid eye drops: Rinderon eye drops 0.01% (betamethasone) 5 times/day → switch to Flumetholon eye drops 0.1% (fluorometholone) 2-3 times/day (taper over 6 months)

Systemic administration: Prednisone 20 mg for a few days, or no administration

CsA: Combined eye drops, continued for several months

Postoperative management of high-risk eyes

Steroid eye drops: Betamethasone 0.1% × 4 times/day → continued for 1 year or more

Systemic steroids: Rinderon injection 0.4% 2 mg once daily IV drip for 3 days from surgery day, then Rinderon tablets 0.5 mg 2 tablets divided in 1, tapered over 2 weeks

CsA: Neoral capsules 25 mg 3 mg/kg/day, trough level 70-100 ng/mL

Systemic administration of immunosuppressive drugs

Cyclosporine A (CsA) is used in high-risk cases such as corneal stromal vascular invasion involving 2 or more quadrants, regrafts, and history of rejection. During systemic administration, maintain trough level at 70-100 ng/mL and monitor systemic side effects including renal function. Continue for about 6 months postoperatively.

In an 18-year-old PKP case with bilateral simultaneous rejection, after remission with IV methylprednisolone pulse, due to steroid response, switched to CsA 1% eye drops and maintained successfully⁵⁾. CsA 1% eye drops allow early tapering of potent steroids in steroid responders and are useful for long-term graft maintenance⁵⁾.

Tacrolimus is used as a switch drug for cases that develop rejection while on oral cyclosporine. Target trough level is 8-10 ng/mL until 2 months postoperatively, then 5-6 ng/mL thereafter (Prograf 0.05-0.1 mg/kg/day). There are reports that 0.03% tacrolimus eye drops are effective in preventing rejection in high-risk corneal transplantation.

Suture management and long-term management after rejection

Loose or broken sutures can trigger both rejection and late infection, so remove them promptly upon discovery. After suture removal, temporarily intensify steroid and antibiotic eye drop treatment. Even after remission, long-term continuation of steroid eye drops is expected to suppress recurrence³⁾.

When starting with betamethasone 0.1%, first continue a maintenance phase of 4 times/day for several months to 1 year, then switch to a low-concentration steroid such as fluorometholone 0.1% and maintain long-term at 1-2 times/day. If intraocular pressure rises, consider switching to loteprednol or adding glaucoma eye drops.

Precautions and side effects in treatment

Acute rejection resolves in over 50% of cases with steroid treatment, but delayed initiation leads to irreversible endothelial cell loss and graft failure. Long-term steroid eye drops carry side effects such as steroid-induced glaucoma, posterior subcapsular cataract, and increased susceptibility to infection. Regular intraocular pressure measurement and monitoring for signs of infection are essential. Systemic administration of cyclosporine or tacrolimus requires monitoring of renal function, blood pressure, blood glucose, and blood drug levels.

Q How is rejection treated in cases with steroid response?

A

If intraocular pressure rises due to steroid response, consider switching from prednisolone acetate to loteprednol, which has less effect on intraocular pressure, or combining with CsA 1% eye drops. CsA 1% eye drops allow early tapering of steroids and are useful for balancing intraocular pressure management and rejection suppression. Concomitant use of glaucoma eye drops is also performed as needed.

6. Pathophysiology and Detailed Mechanisms

Breakdown of Immune Privilege and Delayed-Type Hypersensitivity

The cornea maintains physiological immune tolerance through anterior chamber-associated immune deviation (ACAID). In ACAID, antigen-presenting cells become tolerogenic in a TGF-β-dominant environment, suppressing delayed-type hypersensitivity and complement-fixing antibody production against donor antigens. However, when high-risk factors such as neovascularization, inflammation, or loose sutures are present, this immune privilege is easily disrupted.

The central mechanism of rejection is delayed-type hypersensitivity, and the main effector cells are CD4+ Th1 cells. Activated Th1 cells produce IFN-γ, inducing MHC class II antigen-presenting cells throughout the transplanted cornea, leading to cell-mediated immune response ⁸⁾. The involvement of antibody-mediated mechanisms has also gained attention in recent years, suggesting that anti-HLA antibodies may cause chronic endothelial cell damage via complement activation ¹⁾.

Immunological Differences Between Surgical Techniques

Differences in rejection rates among surgical techniques are mainly due to the amount and antigenicity of donor tissue transplanted ³⁾.

• PKP: Since full-thickness cornea is transplanted, dendritic cells abundant in the superficial stroma and donor epithelium act as a large amount of antigen ³⁾. Loose sutures further increase rejection risk ³⁾.
• DALK: Since donor endothelium is not included, the most severe endothelial rejection does not occur in principle. However, stromal rejection can occur.
• DSAEK: Endothelial transplantation with a carrier of about 50–100 μm of posterior stroma, with less antigen load than PKP. Donor cornea is prepared using a microkeratome, inserted into the anterior chamber with a pull-through technique using a dedicated instrument, and attached with air tamponade.
• DMEK: Transplantation of only the Descemet membrane and endothelium, with minimal antigen load and no sutures, resulting in the lowest rejection rate ³⁾. Rebubbling (air reinjection) after DMEK may be necessary to repair graft detachment; meta-analysis shows it is significantly more frequent in the DMEK group than in the UT-DSAEK group (OR 2.76, 95% CI 1.46–5.22) ²⁾.

Peripheral Anterior Synechiae and Rejection

Peripheral anterior synechiae (PAS) have been noted as a risk factor for rejection after DMEK. In a mouse corneal transplant model, the group with PAS showed significantly increased rejection ⁷⁾. Direct contact between the iris and donor endothelium due to PAS is thought to induce cytotoxic T lymphocyte activity and promote rejection ⁷⁾.

HLA Matching and Immune Response Redundancy

Corneal transplant rejection is primarily mediated by cellular immunity, but rodent studies have identified multiple distinct immune pathways leading to rejection ¹⁾. This redundancy in immune response is considered one reason for inconsistent results in HLA matching studies ¹⁾. Recently, the role of anti-HLA antibodies and antibody-mediated rejection has also gained attention, potentially elucidating mechanisms of late endothelial failure ¹⁾.

Proposed Mechanism of Vaccine-Associated Rejection

COVID-19 vaccination elicits a systemic immune response, inducing SARS-CoV-2 neutralizing antibodies as well as antigen-specific CD8+ and Th1-type CD4+ T cell responses ⁶⁾. This immune activation may trigger rejection of the transplanted cornea through cross-reactivity or non-specific immune activation ⁶⁾. For inactivated vaccines (Sinopharm), the immunogenicity of the adjuvant aluminum hydroxide has been suggested as a possible main cause of rejection ⁹⁾. However, at the meta-analysis level, no increase in rejection after COVID-19 vaccination in solid organ transplantation has been confirmed, and a causal relationship in corneal transplantation has not been established at this time.

7. Latest Research and Future Perspectives (Investigational Reports)

For Patients: Please Read Carefully

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Case reports of corneal transplant rejection associated with COVID-19 vaccines are accumulating worldwide ⁹⁾. A literature review has collected over 20 cases, revealing that the majority are regrafts, onset occurs 1–2 weeks after vaccination, and most recover with steroid treatment ⁹⁾. Prophylactic steroid administration before vaccination has been proposed, but no randomized controlled trials exist, and decisions must be made on a case-by-case basis ⁸⁾⁹⁾.

Regarding the effectiveness of HLA matching, the CTFS II trial prospectively investigated this, but at present, no clear clinical benefit of HLA-DR matching in corneal transplantation has been demonstrated ¹⁾. However, the role of anti-HLA antibodies and antibody-mediated rejection is becoming clearer, which may contribute to elucidating the mechanism of late endothelial failure ¹⁾.

In comparisons between UT-DSAEK and DMEK, both the Sela 2023 meta-analysis ²⁾ and the Dunker 2020 multicenter RCT ¹¹⁾ showed no significant difference in 12-month rejection rates, while the DMEK group achieved better corrected visual acuity. However, graft failure tended to be slightly higher in the DMEK group ²⁾, and the choice of surgical technique should be based on a comprehensive assessment of the patient’s individual ocular pathology, history, and institutional experience.

The following directions are attracting attention for the future.

• Rho kinase inhibitors (ripasudil, netarsudil): Expected to have anti-inflammatory effects and endothelial regenerative capacity, offering the prospect of regenerating corneal endothelium, which was previously considered non-regenerative.
• Preoperative anti-VEGF agents: Investigated for reducing rejection rates in high-risk eyes by inducing regression of corneal neovascularization.
• Cytokine profiling: Efforts are underway to measure cytokine concentrations (e.g., IFN-γ, IL-6, IL-17) in tears and aqueous humor to stratify high-risk patients and provide a basis for individualized immunosuppression.
• Cultured corneal endothelial cell injection therapy: Clinical research is progressing on injecting autologous or allogeneic cultured endothelial cells into the anterior chamber.
• iPS cell-derived corneal cells: The use of allogeneic iPS cell banks with specific HLA types that have low immunogenicity, and the production of cultured corneal epithelial cell sheets have been reported, exploring future rejection-free transplant medicine.
• Gene therapy and immunomodulatory therapy: Novel approaches targeting suppression of antigen presentation by dendritic cells or induction of regulatory T cells are being investigated at the preclinical stage.
• Artificial cornea (Boston KPro): For cases with severe corneal scarring and neovascularization where standard PKP carries an extremely high risk of rejection, artificial corneal replacement is an option.
• Corneal bioprinting: Research is progressing on creating corneal tissue using 3D bioprinters, which is expected to be a technology that solves both donor dependency and rejection reactions.

8. References

1. Armitage WJ, et al. Corneal transplant follow-up study II: HLA class II matching in high-risk penetrating keratoplasty. Br J Ophthalmol. 2019;103(1):132-136.
2. Sela TC, et al. Ultra-thin DSAEK versus DMEK: a systematic review and meta-analysis. BMJ Open Ophthalmol. 2023;8:e001397.
3. American Academy of Ophthalmology Cornea/External Disease Preferred Practice Pattern Panel. Corneal Edema and Opacification Preferred Practice Pattern. San Francisco, CA: American Academy of Ophthalmology; 2019.
4. American Academy of Ophthalmology Cornea/External Disease Preferred Practice Pattern Panel. Corneal Ectasia Preferred Practice Pattern. San Francisco, CA: American Academy of Ophthalmology; 2024.
5. Alsawad HI, Aljufairi FM, Mahmood AH. Unexplained bilateral simultaneous corneal graft rejection in a healthy 18-year-old male. Cureus. 2021;13(4):e14612.
6. Wasser LM, Roditi E, Zadok D, Berkowitz L, Weill Y. Keratoplasty rejection after the BNT162b2 messenger RNA vaccine. Cornea. 2021;40(8):1070-1072.
7. Miyoshi Y, Ono T, Seki S, Toyono T, Kitamoto K, Hayashi T, et al. Corneal graft rejection after Descemet’s membrane endothelial keratoplasty with peripheral anterior synechiae. Case Rep Ophthalmol. 2022;13(1):17-22.
8. Nahata H, Nagaraja H, Shetty R. A case of acute endothelial corneal transplant rejection following immunization with ChAdOx1 nCoV-19 coronavirus vaccine. Indian J Ophthalmol. 2022;70(5):1817-1818.
9. Mohammadzadeh M, Hooshmandi S, Jafari M, Hassanpour K. Presumably corneal graft rejection after COVID-19 vaccination. Case Rep Ophthalmol. 2022;13(2):562-569.
10. Andrade e Andrade ME, Rodrigues JC, Ferreira Junior E, de Lima MHC. Keratoplasty rejection after messenger RNA vaccine (BNT162b2) for COVID-19. Indian J Ophthalmol. 2022;70(8):3134-3136.
11. Dunker SL, Dickman MM, Wisse RPL, Nobacht S, Wijdh RHJ, Bartels MC, et al. Descemet membrane endothelial keratoplasty versus ultrathin Descemet stripping automated endothelial keratoplasty: a multicenter randomized controlled clinical trial. Ophthalmology. 2020;127(9):1152-1159.