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Archivos de la Sociedad Española de Oftalmología

versión impresa ISSN 0365-6691

Arch Soc Esp Oftalmol v.80 n.1 Madrid ene. 2005






Penetrating keratoplasty has emerged as the most common form of solid tissue transplantation with a success rate as high as 90% for uncomplicated first grafts performed in avascular «low-risk» beds with only local immune suppression. This success in low-risk corneal transplantation, however, is overshadowed by the results of corneal grafts placed in «high-risk» beds with rejection rates approaching 70%, even with maximal local and systemic immune suppression (1). To establish an optimal treatment for these corneas, the first hurdle remains the definition of a high-risk cornea. The Collaborative Corneal Transplantation Studies (CCTS) defined «high-risk» as a cornea with two or more quadrants of deep stromal vascularization or one in which a graft had previously been rejected (2). The incidence of rejection increases with both the number of quadrants vascularized and the total number of vessels crossing the proposed graft/donor junction. Together, both immunologic factors, such as previous graft rejection, corneal vascularization, and peripheral anterior synechia; as well as non-immunologic factors, such as ocular surface disease, glaucoma, aqueous tear deficiency, and decreased sensation, increase the risk of graft rejection.

Several unique anatomic and physiologic features of the cornea and the anterior chamber contribute to the immune privilege associated with corneal graft survival. These include the lack of corneal vascularity, the absence of corneal lymphatics, the low expression of MHC antigens by the cornea, the ocular expression of a unique range of immunomodulatory factors and neuropeptides, and the expression of CD95 (Fas) ligand. In addition, until very recently, the cornea was also thought to be devoid of resident antigen presenting cells (APCs), including Langerhans cells (LCs), that was assumed to be a critical component of corneal immune privilege. This paradigm however, was recently modified and it has now been demonstrated that the cornea is indeed endowed with resident APCs that are universally MHC Class II negative in the center, but are capable of expressing Class II antigen after inflammation or transplantation (1). Therefore, it is highly likely that immune privilege is not achieved by the lack of APCs, but rather from a lack of maturation of these cells.

Over the last years, several laboratories have reported the immunologic features of high-risk corneal transplantation, which are characterized by loss of corneal avascularity, the establishment of lymphatic drainage to cervical lymph nodes, migration of LCs into the cornea, and maturation of resident APCs that are able to enhance the immune surveillance. Other features of high-risk recipients include up-regulation of proinflammatory cytokines. There is now overwhelming evidence that nearly every aspect of the normal corneal and ocular physiology that maintains immunologic privilege in the normal setting is lost in high-risk corneal graft recipients.

Although much is being learned in laboratory science about this problem, not much has changed from a clinical standpoint and corneal grafting in high-risk corneas remains a significant challenge. It is both remarkable and sobering to remember that the rate of rejection of corneas grafted into high-risk eyes, exceeds the rate of rejection of kidney, heart and liver grafts and that the most significant contribution to corneal transplant immunotherapy had been the advent of corticosteroids over half a century ago. Intensive topical steroid treatment remains as the main therapy, and for intractable graft rejection, local injection of cyclosporin A is added. Moreover, in the most severe cases of graft rejection, a systemic treatment with large doses of steroids supplemented with cyclosporin A are attempted. Throughout this ever-escalating therapeutic strategy, an ever-escalating set of complications accrue, such as exacerbation of glaucoma, cataracts, corneal thinning, ocular herpes infection and other opportunistic infections. The need for less toxic approaches to prevent and treat immune rejection is therefore apparent and has led to numerous new approaches in studies with orthotopic corneal grafting in animal models and a relatively wide range of possible new treatment strategies have been advanced in the recent years. These include, inhibiting APCs, blocking the activation and action of T cells, modulating the immune response with cytokines and peptides, inducing allospecific tolerance, and blocking the immune access to the graft through inhibition of adhesion molecules and chemotactic cytokines and the reduction of corneal neovascularization. The clinical applicability of these specific promising strategies, however, remains to be tested in clinical trials.

A major accomplishment of modern immunology is the ability to type tissue for HLA class I and class II antigens. Matching donors and recipients for HLA antigens generally improves the survival of solid organ transplants, but evidence that HLA tissue matching improves the fate of corneal allografts is conflicting. There is general agreement that HLA matching does not improve the success of low-risk corneal transplantation, although a few investigators have found a slight benefit of tissue typing in low-risk keratoplasty. Numerous studies have suggested that matching of donors and recipients for HLA-A and HLA-B histocompatibility antigens reduces the likelihood of rejection in high-risk penetrating keratoplasty. The effect of class II matching, however, remains more controversial. Positive effects for HLA-DR matching in high-risk keratoplasty with a long-term survival rate of up to 79% have been reported. In contrast, some UK based studies demonstrated an adverse effect in graft survival with HLA-DR matching, while other studies, including the CCTS, showed no effect of HLA-DR matching at all. Despite the heterogeneity of these data, a meta-analysis of these studies suggests a beneficial effect of MHC class II mismatching in high-risk eyes, but only if the CCTS data are excluded.

To date, the only randomized, prospective controlled clinical trial of histocompatibility in corneal transplantation is the CCTS. It was designed to evaluate the effect of donor-recipient histocompatibility matching and cross-matching on the survival of corneal transplants in high-risk patients. The study was unable to detect any beneficial effect of such tissue matching on the rate of graft failure, rate of reactions, or the rate of failure caused by rejection. The CCTS, however, did found that ABO incompatibility increased the adjusted risk of failure from any cause and failure from rejection. One possible criticism of the CCTS is that it included patients with limbal stem cell deficiency. Although non-rejection related failure was clearly defined in the study, the inclusion of this group could have «diluted» the beneficial effect of HLA matching. Further, the intense steroid treatment used in the CCTS, which suppresses HLA expression, along with closer follow-up examinations could have masked the beneficial effect of HLA matching in high-risk grafts (2).

Previous data from animal studies indicate that graft rejection occurs predominantly via the indirect pathway of allorecognition, in which recipient APCs take up donor peptide and present it to the immune system. This was consistent with the low levels of MHC class II expression and the presumed lack of APCs in the cornea. More recent data, however, have demonstrated the presence of large numbers of resident APCs in the central cornea and it has now been shown that the activation of these resident APCs leads to direct presentation of graft antigens to host T cells in high-risk grafts (3), suggesting that the pathways of sensitization vary significantly between low-risk and high-risk corneal transplantation. These findings raise, once again, the question of the utility of HLA matching in high-risk keratoplasty. Perhaps another carefully designed clinical trial is now necessary to answer this lingering question. In the meantime, it might be prudent to consider ABO matching, given the availability and likelihood of finding a match, while reserving HLA matching for unusual cases with repeated immunological rejection.

1 Department of Ophtalmology & Visual Sciences. University of Louisville. Louisville, KY, United States.



1. Hamrah P, Djalilian AR, Stulting RD. Immunologically High-Risk Penetrating Keratoplasty. In: Kratchmer JH, Mannis MJ, Holland EJ. Cornea. 2nd Edition, Chapter 133. St. Louis: Mosby; 2005; 1619-1635.

2. The collaborative corneal transplantation studies (CCTS). Effectiveness of histocompatibility matching in high-risk corneal transplantation. The Collaborative Corneal Transplantation Studies Research Group. Arch Ophthalmol 1992; 110:1392-1403.

3. Huq S, Liu Y, Benichou G, Dana MR. Relevance of the direct pathway of sensitization in corneal transplantation is dictated by the graft bed microenvironment. J Immunol 2004; 173: 4464-4469.