High-risk Corneal Transplantation: Recent Developments and Future Possibilities

Abstract

HISTORICAL AND GLOBAL SIGNIFICANCE OF CORNEAL TRANSPLANTATION AND FACTORS ASSOCIATED WITH HIGH IMMUNOLOGICAL RISK The landmark report by Eduard Zirm in 1905 of a successful full-thickness corneal transplant in a 45-year-old farm laborer with lime burn preceded, by several decades, the subsequent successes of vascularized organ transplants. 1,2 Following the introduction of topical corticosteroid therapies in the 1950s, corneal transplantation (keratoplasty) has become established as the primary sight-restoring procedure for corneal blindness in developed and developing countries. 3 Furthermore, while partial-thickness (lamellar) keratoplasty has now become the preferred transplant procedure for many corneal disorders, 4 fullthickness allograft remains the most frequently utilized treatment worldwide for corneal conditions associated with significant stromal opacity or vascularization such as bacterial, fungal, or viral infections; severe atopic disorders; ocular trauma and prior graft loss. Corneal opacity Review Abstract. Human corneal transplantation (keratoplasty) is typically considered to have superior short-and long-term outcomes and lower requirement for immunosuppression compared to solid organ transplants because of the inherent immune privilege and tolerogenic mechanisms associated with the anterior segment of the eye. However, in a substantial proportion of corneal transplants, the rates of acute rejection and/or graft failure are comparable to or greater than those of the commonly transplanted solid organs. Critically, while registry data and observational studies have helped to identify factors that are associated with increased risk of corneal transplant failure, the extent to which these risk factors operate through enhancing immune-mediated rejection is less clear. In this overview, we summarize a range of important recent clinical and basic insights related to high-risk corneal transplantation, the factors associated with graft failure, and the immunological basis of corneal allograft rejection. We highlight critical research areas from which continued progress is likely to drive improvements in the long-term survival of high-risk corneal transplants. These include further development and clinical testing of predictive risk scores and assays; greater use of multicenter clinical trials to optimize immunosuppressive therapy in high-risk recipients and robust clinical translation of novel, mechanistically-targeted immunomodulatory and regenerative therapies that are emerging from basic science laboratories. We also emphasize the relative lack of knowledge regarding transplant outcomes for infection-related corneal diseases that are common in the developing world and the potential for greater cross-pollination and synergy between corneal and solid organ transplant research communities.

Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology

“…Despite maximal immune suppression, the failure rate dramatically increases to 50% in recipients with inflamed graft beds. The likelihood of acute rejection and/or graft failure in patients in this "high risk" category is comparable to or larger than that of the commonly transplanted solid organs [2]. Despite intensive study, the heterogeneity of responses to corneal grafts is a poorly understood subject.…”

Lymphatic Trafficking in the Eye: Modulation of Lymphatic Trafficking to Promote Corneal Transplant Survival

“…In addition to acting as transportation conduits, lymphatic vessels also determine the speed and amount of APCs and other cells or cellular debris reaching the regional lymph nodes in a given time [ 48 ]. Since the time window for allograft sensitization after corneal transplantation prior to reestablishment of the ocular immunosuppressive microenvironment is relatively narrow [ 54 , 55 , 56 ], the early reduction of APC trafficking to draining lymph nodes seems to be important for the risk of graft rejections. In addition, interactions between activated lymphatic endothelium and APCs may further activate them [ 48 , 57 ].…”

Kaempferol alleviates corneal transplantation rejection by inhibiting NLRP3 inflammasome activation and macrophage M1 polarization via promoting autophagy

“…Corneal transplantation is currently the only treatment option available [2]. However, the incidence of postoperative immune rejection is still as high as 50% on in ammatory and vascularized beds [3].…”