Corneal graft immunity and rejection recognition

Corneal transplantation is the most common and historically most successful form of solid organ allografting performed in humans. However, immunological graft rejection remains the primary cause of graft failure following penetrating and endothelial keratoplasty. Differentiating reversible immunological rejection from irreversible graft failure is a fundamental clinical competency in anterior segment practice.

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1. Immunobiology of Corneal Immune Privilege & Rejection

Under normal physiological conditions, the cornea enjoys remarkable ocular immune privilege, mediated through multiple anatomical, physiological, and active immunoregulatory mechanisms:

1. Avascularity & Lymphatic Absence: The healthy cornea is completely devoid of blood and lymphatic vessels, depriving antigens of access to regional lymph nodes.
2. Low Expression of Histocompatibility Antigens: Central corneal cells express minimal Major Histocompatibility Complex (MHC) Class I molecules and completely lack MHC Class II molecules (HLA-DR, DP, DQ).
3. Immunomodulatory Cell-Surface Ligands: Corneal cells constitutively express Fas Ligand (FasL / CD95L) and Programmed Death-Ligand 1 (PD-L1). Interacting with Fas and PD-1 on invading activated T cells, they induce rapid T-cell apoptosis.
4. Immunosuppressive Microenvironment: Aqueous humor contains potent immunosuppressive factors: Transforming Growth Factor-beta 2 (TGF-$\beta_2$), alpha-Melanocyte-Stimulating Hormone ($\alpha$-MSH), Vasoactive Intestinal Peptide (VIP), and Calcitonin Gene-Related Peptide (CGRP).
5. Anterior Chamber-Associated Immune Deviation (ACAID): Introduction of soluble foreign antigen into the anterior chamber elicits a systemic down-regulation of delayed-type hypersensitivity (DTH) mediated by regulatory T cells (Tregs: CD4+ CD25+ FoxP3+) generated within the spleen.

The Rejection Cascade: Breakdown of Privilege

When corneal trauma, infection, surgery, or pre-existing disease violates this privilege, rejection proceeds through two distinct arms:

• Afferent Arm (Sensitization): Ingrowth of lymphatic vessels (lymphangiogenesis driven by VEGF-C and VEGF-D) enables passenger donor dendritic cells and host antigen-presenting cells (APCs) to migrate to ipsilateral regional submandibular and cervical lymph nodes. Antigens are presented via direct (donor APCs displaying intact donor MHC) or indirect (host APCs processing donor peptides) pathways.
• Efferent Arm (Effector Attack): Sensitized CD4+ Th1 helper T cells and CD8+ cytotoxic T lymphocytes (CTLs) proliferate, enter the systemic circulation, and traffic back through newly sprouted corneal blood vessels. Within the graft, they release pro-inflammatory cytokines (Interferon-gamma [IFN-$\gamma$], Tumor Necrosis Factor-alpha [TNF-$\alpha$]) and cytotoxic granules (perforin, granzyme B), triggering apoptotic and necrotic destruction of donor corneal cells.

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2. Risk Factors for Corneal Allograft Rejection

Important risk factors include host blood and lymphatic vascularisation, previous rejection or repeat grafting, active surface inflammation, graft proximity to the limbus, glaucoma and complex anterior segment surgery. Risk depends on procedure and indication; numerical rates from different transplant cohorts are not interchangeable. In children, diagnosis, adherence, amblyopia, inflammation and examination difficulties also affect outcomes. Optimise the ocular surface, control infection, document vessels and discuss the practical ability to attend urgent review.

3. Clinical Phenotypes of Corneal Graft Rejection

Corneal graft rejection can target any of the donor cellular layers, presenting as four distinct biomicroscopic phenotypes:

1. Epithelial Rejection

• Biomicroscopy: A faint, elevated, wavy, irregular epithelial rejection line that stains positively with sodium fluorescein. It advances across the donor cornea over days to weeks, as donor epithelial cells are destroyed and replaced by host epithelial cells.
• Symptoms: Often completely asymptomatic or presenting with mild foreign body sensation and conjunctival hyperaemia.
• Clinical Significance: Mildest form of rejection. It does not cause permanent graft failure if isolated, but serves as a critical biological warning sign of host sensitization that may precede endothelial rejection.

2. Subepithelial Rejection

• Biomicroscopy: Krachmer spots—multiple, small ($0.1–0.5\text{ mm}$), discrete, round, subepithelial infiltrates confined strictly to the donor tissue, sparing the recipient host cornea.
• Morphology: Resembles the nummular infiltrates of epidemic keratoconjunctivitis (EKC). Represents a delayed-type hypersensitivity reaction against donor keratocytes in the anterior stroma.

3. Stromal Rejection

• Biomicroscopy: Full-thickness stromal haze, stromal oedema, circumscribed interface inflammation, and deep stromal neovascularisation invading across the graft-host junction. May manifest as a peripheral, crescentic stromal rejection arc.

4. Endothelial Rejection

Endothelial rejection is the most frequent, destructive, and sight-threatening form of allograft rejection. Endothelial cells are post-mitotic; once destroyed by cytotoxic T cells, they cannot regenerate.

• characteristic Biomicroscopic Sign: The Khodadoust Line—a distinct, irregular line of white-yellow keratic precipitates (KPs) on the donor endothelial surface that advances progressively across the graft, typically originating from a vascularised host margin.
• Biomicroscopic Triad:
  1. Behind the Khodadoust line: Endothelial cells are necrotic; the overlying stroma displays dense oedema, Descemet folds, and epithelial microcystic bullae.
  2. Ahead of the Khodadoust line: The donor cornea remains completely compact, thin, and crystal clear.
  3. Anterior Chamber: Pronounced ciliary flush, anterior chamber cells and protein flare, and elevated intraocular pressure.
• Clinical Symptoms: Sudden, profound drop in visual acuity, dull aching periorbital pain, redness, and photophobia.

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