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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplant. Mar 24, 2016; 6(1): 10-27
Published online Mar 24, 2016. doi: 10.5500/wjt.v6.i1.10
High-risk corneal allografts: A therapeutic challenge
Tian Yu, Vijayalakshmi Rajendran, May Griffith, John V Forrester, Lucia Kuffová
Tian Yu, Vijayalakshmi Rajendran, John V Forrester, Lucia Kuffová, Section of Immunity, Infection and Inflammation, Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Sciences, University of Aberdeen, Scotland AB25 2ZD, United Kingdom
May Griffith, Integrative Regenerative Medicine Centre, Department of Clinical and Experimental Medicine, Linköping University, S-58185 Linköping, Sweden
May Griffith, Department of Ophthalmology, Maisonneuve-Rosemont Hospital, Montreal H1T 2M4, Canada
John V Forrester, Ocular Immunology Program, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth WA 6009, Australia
Author contributions: Yu T and Rajendran V contributed equally to this work; Rajendran V and Kuffová L performed the experiments; Yu T and Rajendran V conducted literature review and writing of the manuscript; Griffith M provided intellectual input and critical revision; Forrester JV and Kuffová L provided intellectual input, critical revision and approval of the final version.
Supported by Saving Sight in Grampian, Development Trust of University of Aberdeen, United Kingdom; Action Medical Research United Kingdom (grant SP4328) and Linköping University, Sweden.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Lucia Kuffová, MD, PhD, Section of Immunity, Infection and Inflammation, Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Sciences, University of Aberdeen, Scotland AB25 2ZD, United Kingdom. l.kuffova@abdn.ac.uk
Telephone: +44-012-24437505 Fax: +44-012-24437506
Received: July 30, 2015
Peer-review started: August 5, 2015
First decision: September 21, 2015
Revised: November 4, 2015
Accepted: December 3, 2015
Article in press: December 4, 2015
Published online: March 24, 2016
Processing time: 227 Days and 17.3 Hours
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.

Keywords: “High-risk” grafts; Graft rejection; Systemic immunosuppression; Cell-based immunomodulation; Keratoprosthesis; Collagen-based hydrogels

Core tip: Corneal grafts enjoy a high acceptance rate when performed in “low-risk” host graft beds. This is associated with a relatively weak alloimmune response. However, in “high-risk” hosts where the immunologically quiescent homeostatic environment of the cornea is compromised prior to graft procedure, heightened immune responses significantly increase the risk of graft rejection. Clinical approaches such as tissue matching and long-term immunosuppression could be beneficial in preventing graft rejection especially in “high-risk” settings. In addition, promotion of transplant tolerance by cell-based therapies and use of corneal “substitutes” such as collagen-based hydrogels are promising alternatives for “high-risk” recipients.