The current arsenal & its limits
Corneal graft rejection: when will 21st-century therapeutics arrive?
From non-specific immunosuppression to immunoregulation: from inhibitor to vesicle.
Fondation Adolphe de Rothschild Hospital, Paris · Université Paris Cité.
Corneal transplantation holds a unique place in transplant medicine. It is the oldest: the first successful tissue graft in humans was corneal, performed by Eduard Zirm in 1905. It is also, across all types of transplantation, the most frequent worldwide; the survey by Gain and colleagues counted nearly 185,000 procedures per year, making the cornea the most transplanted human tissue and keratoplasty both the most common and the most reliable allograft [1,2]. It owes much to the cornea’s immune privilege: avascularity, absence of afferent lymphatic drainage, anterior chamber-associated immune deviation — factors that all limit allorecognition. The contrast is stark between the evolution of surgical technique, from penetrating keratoplasty to selective anterior lamellar and endothelial grafts, and the stability of anti-rejection treatments since the mid-20th century. This stability owes in part to the effectiveness of these treatments in most indications; it becomes questionable in situations where they are not enough.
A proven but ageing therapeutic arsenal
In practice, rejection prevention relies almost always on topical corticosteroid therapy, sometimes reinforced by systemic corticosteroids, and, in at-risk cases, on a calcineurin inhibitor (ciclosporin or tacrolimus) given topically. The systemic route for these inhibitors is used only exceptionally in corneal ophthalmology [3,4]. The efficacy of this arsenal is well established: in low-risk grafts, topical corticosteroid therapy alone most often achieves graft survival above 90% at five years. These molecules nonetheless remain old in their design, and their framework of use remains imperfect. Corticosteroids are the reference treatment even though no specialty product holds a dedicated marketing authorization for this indication. Topical tacrolimus, whose retrospective results are encouraging, has no standardized commercial form: in France, only one hospital pharmacy compounds it as a magistral preparation, with other prescriptions relying on TALYMUS (tacrolimus 1 mg/mL, Japanese manufacturer Senju), imported under compassionate-access authorization (formerly ATU) [3]. As for topical ciclosporin, its benefit in high-risk grafts remains debated.
A recent French development qualifies this picture: the industrial-scale production of 2% ciclosporin eye drops. Developed by the pharmacy of Amiens-Picardie University Hospital, this formulation was brought to industrial scale at the request of the ANSM, specifically to standardize hospital preparations that had until then been heterogeneous. The resulting product, CICLOGRAFT (ciclosporin 20 mg/mL), marketed by Laboratoires KÔL, comes in single-dose units storable at room temperature and remains accessible under compassionate use [5]. The progress goes beyond formulation alone. Standardizing the formulation, moving to single-dose units, and eliminating the cold chain improves safety, reproducibility, and comfort for patients treated over several months. It remains, however, the optimization of a calcineurin inhibitor — that is, a refinement within the existing framework.
This framework imposes constraints: multiple daily instillations for six to twelve months, followed by a maintenance dose, with the associated adherence difficulties and identified adverse effects — corticosteroid-induced ocular hypertension, cataract, superinfection. These constraints are proportionate to the benefit obtained in routine grafts; they are less so when that benefit diminishes.
Where the current arsenal falls short: high-risk keratoplasty
This is precisely the case in high-risk grafts. On a vascularized, inflamed recipient bed, immune privilege disappears, and more than half of grafts experience a rejection episode despite intensive postoperative management [6,7]. Neovascularization, and lymphangiogenesis above all, are the cause: they open the afferent pathway of allogeneic sensitization. Irreversible rejection remains here the leading cause of failure for optical grafts [4]. It is in this subgroup, more than in routine grafting, that the search for targets more precise than non-specific immunosuppression is justified.