Development of retrocorneal membrane following pig‐to‐monkey penetrating keratoplasty

Abstract

Introduction Recent reports of long-term survival after wild-type (WT) pig-to-monkey corneal xenotransplantation are encouraging. We experienced the rapid development of retrocorneal membranes, a rare complication after corneal allotransplantation (though seen in infants and young children). The original specific aim of the study was to determine the factors associated with successful (young) pig corneal transplantation in monkeys. However, when it was obvious that retrocorneal membranes rapidly developed, our aims became to determine the factors involved in its development after both WT and GE pig corneal xenotransplantation and to investigate the characteristics of the retrocorneal membrane. Methods Rhesus monkeys were recipients of penetrating keratoplasty using WT and GE pigs (n=2, respectively, 1–3 months-old). Local/systemic steroids were administered for 3 months. Grafts were evaluated by slit-lamp for corneal transparency, edema, and neovascularization. Hematoxylin and eosin, Masson trichrome staining, and immunohistochemical analysis were performed. Gal staining was also carried out to distinguish the origin of the membrane. Results All penetrating keratoplasty recipients developed fibrous retrocorneal membranes in the early post-transplantation period, regardless of whether the graft was from a WT or GE pig. There were no features of rejection, with no cell infiltrate in the graft or anterior chamber during the 3 months follow-up. There was no difference in the clinical course between the two groups (WT or GE corneas). Immunohistochemistry indicated that the retrocorneal membranes were CK-negative, α-SMA-positive, and vimentin-positive, suggesting that they were of fibrous (keratocytic) origin. Also, the membrane was Gal positive, suggesting that it is derived from pig cornea. Conclusions Following pig-to-monkey corneal xenotransplantation, we report that retrocorneal membranes are derived from donor pig keratocytes. Prevention of retrocorneal membranes will be necessary to achieve successful corneal xenotransplantation.

Long‐term survival of full‐thickness corneal xenografts from α1,3‐galactosyltransferase gene‐knockout miniature pigs in non‐human primates

“…By eliminating αGal‐related reaction, GTKO pig corneal grafts should survive longer than wild‐type (WT) grafts . However, previous studies have reported otherwise in non‐human primates (NHPs) . Although the rejection mechanism in GTKO pig corneal xenotransplantation remains controversial, there are two possibilities for graft failure: (a) antibody (Ab)‐mediated rejection may still occur although GTKO lacks αGal or (b) disparity of the corneal thickness may affect survival.…”

“…Donor and recipient corneal thickness must be matched for optimal wound approximation. Genetically engineered non‐miniature pig cornea is thicker than miniature pig cornea of the same age; therefore, younger donors (≤3‐month‐old) were used in previous studies . However, younger donor corneas are too flaccid to handle properly, resulting in severe inflammation .…”

The feasibility and efficacy of preparing porcine Descemet’s membrane endothelial keratoplasty (DMEK) grafts by two techniques: An ex‐vivo investigation for future xeno‐DMEK

“…However, these potent immunosuppressive regimes cannot be applied clinically since they may cause severe side effects in case of long‐term use. Furthermore, the thickness disparity between porcine cornea and host bed may lead to several postsurgical complications which may cause grafting failures, such as shallow anterior chamber, secondary glaucoma, anterior synechia, and retro‐corneal membrane …”

“…Furthermore, the thickness disparity between porcine cornea and host bed may lead to several postsurgical complications which may cause grafting failures, such as shallow anterior chamber, secondary glaucoma, anterior synechia, and retro-corneal membrane. 11,12 Endothelial keratoplasty (EK), only replacing the recipient endothelial layer with healthy endothelium, has become the predominant treatment for endothelial impairments in developed countries. In the US, the number of EK is almost equal to that of penetrating keratoplasty (PKP) nowadays.…”

Xenotransplantation

“…Dong et al recently published their initial results of GTKO.hCD46 pig full-thickness corneal xenografts in NHPs, which were comparable to the survival of wild-type pig corneas [54]. Lee et al provided evidence that the limiting factor of survival of pig corneas was the development of a retrocorneal membrane [55]. The Seoul group recently reported prolonged survival (>389 days) of porcine deep-lamellar corneal xenografts in NHPs under immunosuppressive therapy with anti-CD40mAb (Figure 2) [56].…”