Abstract
Corneal transplantation is among the most successful solid organ transplants. However, despite low rejection rates of grafts in the ‘low-risk’ setting, rejection can be as high as 70% when grafted into ‘high-risk’ recipient beds. Under normal homeostatic conditions, the avascular cornea provides a unique environment that facilitates immune and angiogenic privilege. An imbalance in pro-inflammatory, angiogenic and lymphangiogenic mediators leads to a breakdown in corneal immune privilege with a consequent host response against the donor graft. Recent developments in lamellar and endothelial keratoplasties have reduced the rates of graft rejection even more, while providing improved visual outcomes. The corneal layer against which an immune response is initiated, largely determines reversibility of the acute episode. While epithelial and stromal graft rejection may be treated with topical corticosteroids with higher success, acute endothelial rejection mandates a more aggressive approach to therapy due to the lack of regenerative capacity of this layer. However, current immunosuppressive regimens come with the caveat of ocular and systemic side effects, making prolonged aggressive treatment undesirable. With the advent of biologics, efficacious therapies with a superior side effect profile are on the horizon. In our review we discuss the mediators of ocular immune privilege, the roles of cellular and molecular immune players in graft rejection, with a focus on human leukocyte antigen and antigen presenting cells. Furthermore, we discuss the clinical risk factors for graft rejection and compare rates of rejection in lamellar and endothelial keratoplasties to traditional penetrating keratoplasty. Lastly, we present the current and upcoming measures of therapeutic strategies to manage and treat graft rejection, including an overview of biologics and small molecule therapy.
Highlights
Corneal transplantation is among the most prevalent and successful organ transplants performed worldwide [1] with more than 65,000 corneas transplanted annually [2]
Despite the controversy regarding the therapeutic benefit of histocompatibility leukocyte antigen (HLA) matching in preventing corneal graft rejection [5,28], several reports suggest an association between HLA incompatibility and graft rejection, and the advantage of HLA tissue typing especially in high-risk patients [28,29,30,31,32]
It has been shown that actively rejecting grafts are strongly associated with primed, donor HLA-class I-specific cytotoxic T cells, making a strong case in favor of HLA-A and –B typing for high-risk transplant patients [29,33,34,35,36]
Summary
Corneal transplantation is among the most prevalent and successful organ transplants performed worldwide [1] with more than 65,000 corneas transplanted annually [2]. MHC-I antigens are expressed by corneal epithelial, stromal and endothelial cells. Corneal DCs play a critical role in graft rejection through their ability to regulate T cell responses to both self and foreign antigens in the donor button, based on molecular cues received from the tissue microenvironment [21].
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