High-risk corneal allografts: A therapeutic challenge

Abstract

Corneal transplantation is the most common surgical procedure amongst solid organ transplants with a high survival rate of 86% at 1-year post-grafting. This high success rate has been attributed to the immune privilege of the eye. However, mechanisms originally thought to promote immune privilege, such as the lack of antigen presenting cells and vessels in the cornea, are challenged by recent studies. Nevertheless, the immunological and physiological features of the cornea promoting a relatively weak alloimmune response is likely responsible for the high survival rate in "low-risk" settings. Furthermore, although corneal graft survival in "low-risk" recipients is favourable, the prognosis in "high-risk" recipients for corneal graft is poor. In "high-risk" grafts, the process of indirect allorecognition is accelerated by the enhanced innate and adaptive immune responses due to pre-existing inflammation and neovascularization of the host bed. This leads to the irreversible rejection of the allograft and ultimately graft failure. Many therapeutic measures are being tested in pre-clinical and clinical studies to counter the immunological challenge of "high-risk" recipients. Despite the prevailing dogma, recent data suggest that tissue matching together with use of systemic immunosuppression may increase the likelihood of graft acceptance in "high-risk" recipients. However, immunosuppressive drugs are accompanied with intolerance/side effects and toxicity, and therefore, novel cell-based therapies are in development which target host immune cells and restore immune homeostasis without significant side effect of treatment. In addition, developments in regenerative medicine may be able to solve both important short comings of allotransplantation: (1) graft rejection and ultimate graft failure; and (2) the lack of suitable donor corneas. The advances in technology and research indicate that wider therapeutic choices for patients may be available to address the worldwide problem of corneal blindness in both "low-risk" and "high-risk" hosts.

Biomaterials-enabled cornea regeneration in patients at high risk for rejection of donor tissue transplantation

“…41 Here, bridging the wound gape with an organized matrix comprising aligned type III collagen, 22 however, appears to provide a template for controlled in-growth of stromal cells that in turn allows for regeneration of an optically clear cornea. Furthermore, complications such as graft rejection (45% in high-risk patients) are likely elicited by the vascularized or inflamed host cornea reacting against the presence of allogeneic cells, 42 were circumvented by use of cell-free implants. The inflammation inhibiting MPC networked within the implants most likely contributed to the capacity of RHCIII-MPC implants to remain quiescent in the immunogenic corneas, allowing stable restoration of the ocular surface.…”

Management of high-risk corneal transplantation

“…40,111 An avascular, non-inflamed corneal host, termed as low risk (LR) corneal transplantation, can expect a 5-year survival rate of 90% with only topical immunosuppression. 163 However, the survival rate dramatically decreases to below 35% in inflamed, vascularized host beds, so-called high risk (HR) corneal transplantation. 164,166 …”

The Balance of Th1/Th2 and LAP+Tregs/Th17 Cells Is Crucial for Graft Survival in Allogeneic Corneal Transplantation

“…In a cohort study of 10,952 cases, the graft survival rate 1 year after penetrating keratoplasty is as high as 86% [ 2 ]. However, in some circumstances such as inflammation, neovascularization, or infections in corneal graft beds, the immune privilege of corneal allografts can be abolished [ 3 ]. Despite the local and systemic corticosteroid and immunosuppressive therapy, immune rejection is still the leading cause of corneal allograft failure after penetrating keratoplasty [ 4 ].…”