Corneal Allograft Rejection and Failure
In uncomplicated or “low risk” penetrating keratoplasty primary grafts, the survival rate with local immune suppression has been reported to be as high as 95% at 5 years . This remarkable degree of success is achieved by the “immune privileged” status of the cornea, which is caused by an aggregate of factors including :
- absence of vascularity that hinders delivery of immune elements
- absence of corneal lymphatics that prevents delivery of antigens to T cells in lymph nodes
- expression of FAS ligand that can induce apoptosis of stimulated Fas+T cells
- an unusually low expression of MHC antigens
- a unique spectrum of immunomodulatory factors that inhibit T cell and complement activation
In contrast, “high-risk” recipients, such as those with vascularization of the cornea, the failure rate can easily exceed 35% at three years . Despite being an “immunologically privileged” site, the most common cause of graft failure is irreversible, immunologic allograft rejection.
Definition of rejection vs failure:
The term graft rejection refers to a specific immunologic response of the host to the donor corneal tissue. It should be distinguished from other non-immune mediated graft failures, such as primary donor failure. Diagnosis of rejection should only be made in grafts that have remained clear for at least 2 weeks following surgery. The incidence of rejection is greatest in the first year-and-a-half following transplant but can occur up to 20 years or more after surgery. Guilbert et al reported an average keratoplasty-to-rejection time of 19.8 ± 20.4 months (among 299 patients who experienced a rejection episode). The progression from rejection to failure was 49% .
Clinical signs of graft rejection, from most to least common, include:
- corneal edema
- keratic precipitates on the corneal graft but not on the peripheral recipient cornea
- corneal vascularization
- stromal infiltrates
- a Khodadoust line
- an epithelial rejection line
- subepithelial infiltrates
A Khodadoust line separates immunologically damaged endothelium from unaffected endothelium. In the area of damage, the endothelium is decompensated resulting in stromal and epithelial edema. The diagnosis of immunologic graft failure is made if signs of rejection do not clear within 2 months of treatment.
Forms of immune rejection:
There are several forms of immune rejection including epithelial, subepithelial, endothelial, and mixed. Epithelial rejection occurs in roughly 2% of graft rejections.  It begins as a line located near engorged limbal vessels, with migration across the graft-recipient interface. The line consists of lymphocytes, plasma cells, and neutrophils. These lines can precede endothelial rejection by days to weeks. Subepithelial rejections are the least common type of rejection with an occurrence rate of 1% . They are deeper infiltrates caused by rejection of stromal keratocytes. They are randomly distributed in the central cornea, and can occur along an epithelial rejection line or alone. They may also precede endothelial graft rejection, as early as 6 weeks or as late as 2 years after transplantation.
The most common cause of graft rejection is endothelial rejection, occurring in 50% of rejection episodes . Endothelial rejection consists of a line of KPs beginning inferiorly at the graft-host junction and marching superiorly. The limbus may be hyperemic, with an anterior chamber reaction but cells may not be visible due to a diffusely edematous cornea. Finally, a mixed rejection occurs in 30% of episodes .
Transplant rejection is one of the most difficult complications to manage after keratoplasty. The management and likelihood of reversibility is largely determined by the corneal layer affected.
Topical 1% prednisolone acetate is the primary treatment for acute graft rejection and as post operative prophylactic therapy for high risk transplant recipients. For epithelial and subepithelial rejections, which have a higher rate of reversibility, topical corticosteroids can be used six times per day, with a tapered dosing over 6-8 weeks . In contrast, severe endothelial rejection requires topical corticosteroids prescribed hourly (prednisolone acetate 1% q1h or difluprednate 0.05% q2h) in combination with systemic therapy; either 40 to 80mg of oral prednisone daily or a single-pulse or three-pulse intravenous dose of 500mg of methylprednisolone with or without subconjunctival betamethasone 3mg in 0.5mL .
Given the high side effect profile of prolonged corticosteroid use including, cataract formation, glaucoma, impaired wound healing, and immunosuppression, alternative therapeutics are being investigated and becoming more available.
Calcineurin inhibitors, including cyclosporine (CsA) and tacrolimus (FF-506), are viable options for patients in whom corticosteroids are contraindicated. Although the efficacy of cyclosporine A (0.5%) is mixed; it may be substituted for topical corticosteroids to aid in the management of steroid response and post-keratoplasty glaucoma by lowering the mean IOP by 8.2 mmHG while maintaining graft clarity in 88% of patients . However, there was a rejection rate of 12% (6 out of 52 eyes) of patients while on topical cyclosporine alone, 5 of which were reversed with the reintroduction of topical corticosteroids . Tacrolimus can be used topically or systemically. Randomized clinical trials have demonstrated that topical tacrolimus (0.06%) used three times per day for 6 months was superior to topical steroids in preventing rejection episodes (100% vs. 84%) in low-risk patients (8). Systemic administration of tacrolimus (2–12mg daily) is also beneficial in preventing and treating graft rejection in high-risk patients, with a clear graft survival of 65% .
Corneal neovascularization is a strong determinant of graft survival and poses a challenge to reinstating ocular immune privilege after surgery. Fasciani et al demonstrated promising results of using anti-VEGF agents as a preconditioning treatment in patients affected by high immune risk and corneal neovascularization . Compared to controls that directly underwent penetrating keratoplasty, patients who underwent three subconjunctival intrastromal injections of 5 mg in 0.2 ml Bevacizumab experience no episodes of corneal graft rejection at a mean follow up of 26 months. In contrast six of thirteen eyes (46%) in the control group showed evidence of graft rejection at a mean follow up of 3.8 months.
- Hjortdal J, Pedersen IB, Bak-nielsen S, Ivarsen A. Graft rejection and graft failure after penetrating keratoplasty or posterior lamellar keratoplasty for fuchs endothelial dystrophy. Cornea. 2013;32(5):e60-3.
- Dana MR, Qian Y, Hamrah P. Twenty-five-year panorama of corneal immunology: emerging concepts in the immunopathogenesis of microbial keratitis, peripheral ulcerative keratitis, and corneal transplant rejection. Cornea. 2000;19(5):625-43.
- Bartels MC, Doxiadis II, Colen TP, Beekhuis WH. Long-term outcome in high-risk corneal transplantation and the influence of HLA-A and HLA-B matching. Cornea. 2003;22(6):552-6.
- Guilbert E, Bullet J, Sandali O, Basli E, Laroche L, Borderie VM. Long-term rejection incidence and reversibility after penetrating and lamellar keratoplasty. Am J Ophthalmol. 2013;155(3):560-569.e2.
- Qazi Y, Hamrah P. Corneal Allograft Rejection: Immunopathogenesis to Therapeutics. J Clin Cell Immunol. 2013;2013(Suppl 9).
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- Perry HD, Donnenfeld ED, Acheampong A, Kanellopoulos AJ, Sforza PD, et al. Topical Cyclosporine A in the management of postkeratoplasty glaucoma and corticosteroid-induced ocular hypertension (CIOH) and the penetration of topical 0.5% cyclosporine A into the cornea and anterior chamber. CLAO J. 1998; 24:159–165.
- Joseph A, Raj D, Shanmuganathan V, Powell RJ, Dua HS. Tacrolimus immunosuppression in high-risk corneal grafts. Br J Ophthalmol. 2007; 91:51–55.
- Fasciani R, Mosca L, Giannico MI, Ambrogio SA, Balestrazzi E. Subconjunctival and/or intrastromal bevacizumab injections as preconditioning therapy to promote corneal graft survival. Int Ophthalmol. 2014.
Surendar Dwarakanathan MD, (editor)