ABSTRACT Corneal transplantation is not invariably successful despite the anterior chamber of the eye being an immunologically privileged site. Inflammation erodes privilege. Other than by

reducing inflammation through meticulous surgery, careful postoperative surveillance, and effective topical corticosteroids in the postoperative phase, there is little that a surgeon can do

to improve the outlook for the majority of patients receiving corneal transplants. For patients at appreciable risk, HLA Class I matching may help where it is available. So too will systemic

immunosuppression where it can be justified. Despite these measures, the results of corneal transplantation have not shown the improvement seen in solid organ transplantation over the last

practice, normal corneas are not grafted into normal recipient beds. The closest a clinician comes to this is grafting someone for keratoconus or stromal dystrophy. In these cases, graft

survival is almost invariably prolonged. However, many patients requiring a corneal graft have acquired corneal conditions and for this group of patients, prolonged graft survival occurs

less frequently. In Australia, only 31% of corneal grafts are performed for keratoconus and less than 1% are carried out for stromal dystrophies.1 The majority of corneal transplants are

carried out for acquired corneal conditions. In patients with acquired corneal disease, immunological privilege is eroded. Erosion of corneal privilege leaves the graft prone to allograft

rejection, the commonest reason for corneal graft failure. The degree of erosion of privilege is related to the nature of the underlying disease. In some conditions and circumstances, the

erosion of graft privilege and the tendency to allograft rejection is such that graft failure is almost inevitable. In others, the erosion is much less and prolonged graft survival can occur

but is not invariable. A comprehensive evaluation of the clinical factors associated with a higher risk of corneal graft failure is made in the regular reports of the Australian Corneal

Graft Register and assessed by multivariate analysis.2 The clinical factors shown to be related to the risk of corneal graft failure are presented in Table 1. Those for whom the chance of

prolonged survival is reduced are considered high-risk patients. Just how this high-risk group is defined depends on how high one wishes to put the bar. Any patient having a graft for an

acquired condition is at a higher risk of failure compared to someone having a graft for keratoconus. This risk is much higher if the recipient cornea has recently been inflamed, is inflamed

at the time of surgery, or subsequently becomes inflamed. There is some debate as to what constitutes a high-risk corneal graft. This is evident from the criteria used to admit patients to

treatment trials where there is considerable variation in the criteria used. For the purposes of this discussion, we have adopted an arbitrarily determined categorization that we use in our

clinical practice. It is based on consideration of factors shown to be associated with graft survival in the Australian Corneal Graft Register and presented in Table 2. A distinction must be

made between a high-risk graft and a patient at high risk. A high-risk graft is one that is likely to fail. The risk faced by a patient is a more complicated consideration because for a

patient the concept of risk entails not only the probability of a complication occurring but the consequence of its occurrence. For this reason, one-eyed patients are at a higher risk from

eye surgery than binocular patients. One also has to take into account the consequences of any treatment other than the surgery. Some treatments that may be used for patients with high-risk

corneal grafts, such as systemic immunosuppression, come with significant risks. The management of patients needing corneal transplantation is therefore determined by an assessment of the

benefits of a successful outcome, of the risk of graft failure, and the potential consequences of any supporting therapies that might be considered. IMMUNE PRIVILEGE AND THE CORNEAL

ALLOGRAFT RESPONSE Inflammation in the recipient graft bed, or subsequently in the graft, erodes graft rejection and predisposes to allograft rejection and graft failure. An appreciation of

how inflammation erodes corneal privilege and mechanisms of corneal allograft rejection is required as a basis for proposing strategies to decrease the impact of immunological rejection on

graft survival. A number of factors contribute to immunological privilege in the cornea and anterior segment of the eye. * 1 _The blood–eye barrier_. The normal cornea is somewhat remote

from the intravascular space. Only the most peripheral cornea is directly dependent on circulation for nutrition and respiration. The central cornea relies on the tear-film and the aqueous

humour for its maintenance. The aqueous is supported by the vascular iris, but there is no free exchange between the intravascular space and the aqueous. The constituents of the aqueous get

there by a process of active secretion. This separation of the ocular tissues and the intravascular space is referred to as the blood–eye barrier.3,4,5 * 2 _Absence of blood vessels and

lymphatics._ The normal cornea is devoid of blood vessels and lymphatics. The absence of blood vessels and lymphatics interferes with both the afferent and efferent arm of the immune

response.6,7,25 * 3 _Modest expression of HLA._ There is some Class I expression on epithelial cells, stromal keratocytes, and corneal endothelial cells. There is also modest Class II

expression on Langerhans cells in the peripheral epithelium and interstitial dendritic cells in the peripheral stroma.8 ABO antigens are present on epithelial cells.9,10 Transplantation

experiments in rats demonstrate that it is the minor antigens that are important in the corneal allograft response rather than Class I or II. * 4 _Scarcity of antigen processing cells_. The

normal cornea contains few mature cells capable of presenting antigens to the host immune system. There are Langerhans cells in the epithelium11,12 and interstitial dendritic cells in the

peripheral cornea,13,14 but very few become involved in the operative field with conventional corneal grafting. * 5 _Constitutive expression of Fas-ligand (CD95L)._ Only privileged sites

constitutively express Fas-Ligand. The presence of this entity promotes apoptosis in cells bearing Fas, such as immunocytes.15,16,17 * 6 Immunosuppressive cytokines in aqueous humour, for

example, transforming growth factor TGFb,18,19 alpha-melanocyte-stimulating hormone _α_MSH,20 and vasoactive intestinal peptide VIP 21 present in normal aqueous humor. * 7 _Anterior

chamber-associated immune deviation._ Antigens introduced into the anterior chamber of the eye produce antigen-specific suppression of delayed hypersensitivity.22 Some of these factors that

contribute to the immune privilege in the anterior eye are altered by inflammation. Inflammation breaks down the blood–eye barrier. An increase of the leakiness of blood vessels is a

fundamental aspect of inflammation. Any inflammation in the anterior segment of the eye results in egress of cells and proteins into the extravascular space.23,24 Chronic inflammation can

result in the development of new blood vessels and lymphatics.25 The presence of new vessels in the cornea is easily seen clinically and is associated with an increased risk of corneal

allograft rejection.26 There is also an increased expression of HLA antigens in the cornea under inflammatory conditions.27,28 In addition, there is an accumulation of bone-marrow-derived

cells in the cornea with inflammation.22,25 These cells may persist for many years after an inflammatory event. Perhaps the cornea always has higher cell counts after inflammation and never

returns to normal. The number of bone-marrow-derived cells in the recipient cornea is related to the probability of corneal graft failure from rejection.29 When corneal graft privilege is

sufficiently eroded, allograft rejection can occur. There is little a clinician can do to maintain corneal privilege other than suppress inflammation. This is made possible by reducing

corneal trauma to a minimum, by exemplary microsurgical technique, prompt attention to episodes of intercurrent inflammation such as blepharitis or loose sutures, and the use of

anti-inflammatory medication, particularly topical corticosteroids. MECHANISMS OF CORNEAL ALLOGRAFT REJECTION An idealized model of allograft rejection can be constructed from clinical

observations and experimental inferences. The process has some important differences from other organ systems. Both major and minor transplantation antigens seem capable of providing the

starting point for the corneal allograft response.30 It is the bone-marrow-derived cells, the interstitial dendritic cells, that process alloantigens and present them to the host immunocyte.

This occurs in the ocular environs and local lymph nodes.31,32 The second step in the afferent arm of the corneal allograft response is T-cell activation. This occurs when a foreign protein

has been digested in fragments within a phagocytic cell and presented on the cell surface in conjunction with host HLA molecules to a host naive immunocyte. Once activated, an immunocyte

can take on a number of activities related to immunity, such as regulation of immune responses, delayed-type hypersensitivity reactions, and specific lysis of cells. One of the activities of

T lymphocytes is the promotion of clonal expansion. Clonal expansion occurs in draining lymph nodes, and for the cornea the relevant nodes are in the face and the neck.32 The efferent arm

of the corneal allograft response is directed at all components of the cornea, but the endothelial cell monolayer is the most susceptible.33 It has limited capacity for repair. Cell damage

occurs as a result of mechanisms specifically aimed at cells bearing nonself antigens and through nonspecific mechanisms. A summary of the relevant aspects of the corneal allograft response

is presented in Figure 1. Since it is not possible to specifically enhance corneal privilege—only generic strategies to minimize inflammation are practical—surgeons are left with abrogating

the corneal allograft response as the only feasible approach to improve the outlook for patients having high-risk corneal grafts. There are only limited options for achieving this:

minimizing inflammation, reducing relevant immunogenetic differences between donor and host by antigenic matching, and by suppressing host immunoreactivity. STRATEGIES FOR DECREASING THE

EFFECT OF THE CORNEAL ALLOGRAFT RESPONSE EFFECTIVE ANTI-INFLAMMATORY MEASURES Effective microsurgery can reduce postoperative inflammation and so too can the use of topical anti-inflammatory

measures. The time-honoured way of achieving this is with topical corticosteroids. Anecdotal reports suggest that the outcome of corneal transplantation improved dramatically with the

introduction of these agents in the 1960s. Unfortunately, the optimal dose of topical steroids for patients having corneal grafts has not been agreed upon and there is considerable variation

in the way clinicians use these drugs. The unexpectedly good results reported in the Collaborative Corneal Transplantation Study (CCTS)34 in both the antigen-matched and control group have

been attributed to the high doses of topical corticosteroids used in the postoperative period.35 This was considered to be higher than used by most surgeons in their routine practice. Even

when topical corticosteroids are used at close to the maximal tolerated dose, they are only partially effective. The rejection rates for high-risk patients remain unacceptably high despite

high doses of topical corticosteroids. HLA MATCHING There is argument about the place of conventional HLA matching for corneal transplantation, particularly since the unexpected findings of

the CCTS.34 The results of this study have been controversial. They reported no advantage from Class I and II matching but a benefit from ABO matching. These findings for Class I and II

matching contradict earlier studies. This has been attributed to a number of factors, including the high doses of topical corticosteroids used in the postoperative period and insufficiently

accurate tissue typing. The benefit seen with ABO matching is real, surprising, and worthy of further investigation. Despite the findings of the CCTS the weight of evidence from published

studies suggests a modest effect for Class I.35,36,37,38,39 The effect of Class II matching is more equivocal and there are reports to suggest an inverse response as well as a beneficial

response.40,41,42,43 (An inverse response is not completely unexpected since indirect presentation of antigen, as occurs in the corneal allograft response, is Class II restricted.) There is

also experimental evidence that minor antigens are relatively more important than in other forms of clinical transplantation. However, even if the modest benefits of matching are to be

pursued, the logistics of achieving acceptable matches is complicated and time consuming. For many patients, the prolonged waiting time for a matched graft is unacceptable considering the

limited benefits from the process. SYSTEMIC IMMUNOSUPPRESSION Although systemic immunosuppression is widely used in other forms of clinical transplantation, there are only limited reports of

the effectiveness of this approach for corneal transplantation. The most convincing study demonstrated enhanced graft survival in patients who received systemic cyclosporin for a year

compared to groups that received it for only 4 months and a third group that did not receive cyclosporin at all.44,45 Although no major side effects were reported in this study, our

experience is that virtually all patients who receive systemic immunosuppressive doses of the drug develop some drug-related complication. There is the risk of developing potentially

overwhelming infection, even with short-term use, and there is the issue of neoplasia, particularly with long-term administration. Skin and hair changes are common, so too is hypertension.

With long-term therapy, nephrotoxicity is troublesome. There are no large studies to support the use of antiproliferative agents along with systemic cyclosporin, an approach used widely in

solid organ transplantation. Despite the lack of hard evidence, we prefer this approach. The combination of a calcineurin blocker (cyclosporin or FK506) and an antiproliferative agent

(azothioprine or mycophenolate) is widely used in transplantation and has been shown to be more effective than cyclosporin alone. There is no particular regimen that has been shown to be

preferable for patients with high-risk corneal grafts. Nor has the period of time required for immunosuppression to maximize graft survival been determined. Our policy has been to use the

same regimen that is used for essential organ transplantation in our institution. This facilitates prescribing as well as efficacy and toxicity surveillance. We use cyclosporin and

azothioprine or mycofenolate for 1 year unless the drugs are poorly tolerated. It must be emphasized that the documented risks associated with this approach are not acceptable for many

patients having corneal transplants. Since the consequences of complications of immunosuppression may be life threatening, this approach is only acceptable for patients who are blind for the

want of a functioning graft and are prepared to risk a potentially fatal outcome to achieve an improvement in vision.46 A summary of the options available to surgeons managing patients with

high-risk corneal transplants is presented in Table 3. TREATMENT OF CORNEAL ALLOGRAFT REJECTION—GRAFT RETRIEVAL Many grafts that are subjected to an allograft response are lost. For those

who recover, the prospects for long-term survival are reduced.1,2 Rejection episodes are significant events in the life of a graft, and demand prompt attention and effective treatment. It

has been shown that corticosteroids, delivered as an intravenous pulse, retrieve more rejection episodes than oral steroids. Whether this form of treatment reduces the tendency for

subsequent rejection is unknown.47 NOVEL APPROACHES TO IMMUNOMODULATION Antibody-based therapies have an established place in most branches of clinical transplantation, but have not found a

place in corneal transplantation to date. Heterologous antilymphocyte serum or globulin has been used for essential solid organ grafts for many years. More recently, monoclonal antibodies

have been used. OKT3 is used for the treatment of allograft rejection in solid organ transplantation. This approach has not found a place in the treatment of corneal allograft rejection

although one group has reported the use of monoclonal antibodies administered by injection into the anterior chamber of the eye.48,49 More recently, there have been anecdotal reports of

monoclonal antibodies, CAMPATH-1H (anti-CD52)50,51 and anti-CD25,52 given systemically to successfully suppress clinical corneal allograft rejection. As promising as these developments are,

they bring with them the limitations of systemic administration and systemic side effects. Desirable attributes of any novel therapies for corneal transplantation include increased

specificity of immune suppression and local administration. To achieve this, any proposed interference with the allograft response should be proximal in the afferent limb—at the point of

antigen processing and generation—with the hope of achieving suppression of the response to only the relevant alloantigens. Local administration of therapeutic agents as eye drops would also

convey advantage. Local administration limits toxicity to the point of application, and there are the additional advantages of ease of administration and low cost. Two developments that

show promise of satisfying these requirements are the development of monoclonal antibody fragments directed at targets in the immune system53 and the use of gene therapy to modify the

allograft response by influencing cytokine production.54 CONCLUSION There is room for improvement in the outcome of corneal transplants, particularly for patients receiving grafts for

conditions other than keratoconus and stromal dystrophies. Corneal transplantation has not shown the steady improvements that have been seen in other branches of clinical transplantation

because the developments in clinical therapies that have brought about these improvements are not directly applicable to corneal transplantation. To achieve optimal results for corneal

transplantation, it is necessary to select cases carefully to ensure that patients have the greatest chance of improving their functional (binocular) vision at the least personal risk. For

the most part, this means avoiding corneal transplantation in patients who have normal vision in the contralateral eye. More heroic measures can be considered for patients who are blind but

for the need of a clear corneal graft. In all patients receiving a corneal graft, effective anti-inflammatory measures, and in particular the use of topical corticosteroids in the maximal

tolerated dose in the postoperative period, are mandatory. Matching for Class I antigens is also justified where the service is available and it is reasonable for the patient to wait the

time predicted to achieve a helpful match. In some patients, systemic immunosuppression is desirable. This is a small group of patients with clinical features indicating allograft rejection

is likely, who are in need of a clear graft to achieve functional vision, and who are fit and understand the implications of systemic immunosuppression. Even when all these measures are

possible, graft failure because of allograft rejection, and other nonimmunological processes, still occurs. More research and development is needed. Improvements in antigen matching,

anti-inflammatory measures, and immunomodulation that are applicable to clinical corneal allograft rejection are required. REFERENCES * Williams KA, Muehlberg SM, Lewis RF, Giles LC, Coster

DJ . _Report from the Australian Corneal Graft Registry 1996_. Mercury Press: Adelaide, 1997, pp 1–131. Google Scholar  * Williams KA, Muehlberg SM, Bartlett CM, Esterman A, Coster DJ .

_Report from the Australian Corneal Graft Registry 1999_. Snap Printing: Adelaide, 2000, pp 1–137. Google Scholar  * Dernouchamps JP, Heremans JF . Molecular sieve effect of the

blood–aqueous barrier. _Exp Eye Res_ 1975; 21: 289–297. Article  CAS  PubMed  Google Scholar  * Maurice D, Mishima S . Ocular pharmacokinetics. In: Sears M (ed). _Pharmacology of the Eye_.

Springer-Verlag: Berlin, 1984, pp 19–116. Chapter  Google Scholar  * Kuchle M, Nguyen NX, Naumann GO . Aqueous flare following penetrating keratoplasty and in corneal graft rejection. _Arch

Ophthalmol_ 1994; 112: 354–358. Article  CAS  PubMed  Google Scholar  * Barker CF, Billingham RE . Immunologically privileged sites and tissues. In: Porter R, Knight J (eds). _Corneal Graft

Failure Ciba. Foundation Symposium 15 (new series)_. Elsevier: Amsterdam; Excerpta Medica: North-Holland, 1973, pp 79–104. Google Scholar  * Medawar P . Immunity of homologous grafted skin

III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. _Br J Exp Pathol_ 1948; 29: 58–69. CAS  PubMed  PubMed Central 

Google Scholar  * Whitsett CF, Stulting RD . The distribution of HLA antigens on human corneal tissue. _Invest Ophthalmol Vis Sci_ 1984; 25: 519–524. CAS  PubMed  Google Scholar  * Nelken E,

Michaelson IC, Nelken D, Gurebitch J . ABO antigens in the human cornea. _Nature_ 1956; 177: 840. Article  Google Scholar  * Salisbury JD, Gebhardt BM . Blood group antigens on human

corneal cells demonstrated by immunoperoxidase staining. _Am J Ophthalmol_ 1981; 91: 46–50. Article  CAS  PubMed  Google Scholar  * Jager MJ . Corneal Langerhans cells and ocular immunology.

_Reg Immunol_ 1992; 4: 186–195. CAS  PubMed  Google Scholar  * Baudouin C, Brignole F, Pisella PJ, Becquet F, Philip PJ . Immunophenotyping of human dendriform cells from the conjunctival

epithelium. _Curr Eye Res_ 1997; 16: 475–481. Article  CAS  PubMed  Google Scholar  * Williams KA, Ash JK, Coster DJ . Histocompatibility antigen and passenger cell content of normal and

diseased human cornea. _Transplantation_ 1985; 39: 265–269. Article  CAS  PubMed  Google Scholar  * Catry L, Van den Oord J, Foets B, Missotten L . Morphologic and immunophenotypic

heterogeneity of corneal dendritic cells. _Graefes Arch Clin Ex Ophthalmol_ 1991; 229: 182–185. Article  CAS  Google Scholar  * Wilson SE, Li Q, Weng J, Barry-Lane PA, Jester JV, Liang Q _et

al_. The Fas-Fas ligand system and other modulators of apoptosis in the cornea. _Invest Ophthalmol Vis Sci_ 1996; 37: 1582–1592. CAS  PubMed  Google Scholar  * Griffith TS, Yu X, Herndon

JM, Green DR, Ferguson TA . CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance. _Immunity_ 1996; 5: 7–16. Article  CAS  PubMed  Google Scholar

  * Stuart PM, Griffith TS, Usui N, Pepose J, Yu X, Ferguson TA . CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. _J Clin Invest_ 1997; 99: 396–402. Article

  CAS  PubMed  PubMed Central  Google Scholar  * Wilbanks GA, Mammolenti M, Streilein JW . Studies on the induction of anterior chamber-associated immune deviation (ACAID). III. Induction of

ACAID depends upon intraocular transforming growth factor-beta. _Eur J Immunol_ 1992; 22: 165–173. Article  CAS  PubMed  Google Scholar  * D'Orazio T, Niederkorn JY . A novel role for

TGF-beta and IL-10 in the induction of immune privilege. _J Immunol_ 1998; 160: 2089–2098. CAS  PubMed  Google Scholar  * Taylor AW, Streilein JW, Cousins SW . Alpha-melanocyte-stimulating

hormone suppresses antigen-stimulated T cell production of gamma-interferon. _Neuroimmunomodulation_ 1994; 1: 188–194. Article  CAS  PubMed  Google Scholar  * Taylor AW, Streilein JW,

Cousins SW . Immunoreactive vasoactive intestinal peptide contributes to the immunosuppressive activity of normal aqueous humor. _J Immunol_ 1994; 153: 1080–1086. CAS  PubMed  Google Scholar

  * Streilein JW . Peripheral tolerance induction: lessons from immune privileged sites and tissues. _Transplant Proc_ 1996; 28: 2066–2070. CAS  PubMed  Google Scholar  * Williams KA, Coster

DJ . Rethinking immunological privilege: implications for corneal and limbal stem cell transplantation. _Mol Med Today_ 1997; 3: 495–515. Article  CAS  PubMed  Google Scholar  * Kuchle M,

Nguyen NX, Naumann GO . Aqueous flare following penetrating keratoplasty and in corneal graft rejection. _Arch Ophthalmol_ 1994; 112: 354–358. Article  CAS  PubMed  Google Scholar  * Collin

HB . Endothelial cell lined lymphatics in the vascularized rabbit cornea. _Invest Ophthalmol_ 1996; 5: 337–354. Google Scholar  * Coster DJ . Factors affecting the outcome of corneal

transplantation. _Ann R Coll Surg Engl_ 1981; 63: 91–97. CAS  PubMed  PubMed Central  Google Scholar  * Treselet PA, Foulks GN, Sanfilippo F . The expression of HLA antigens by cells in the

human cornea. _Am J Ophthalmol_ 1984; 98: 763–772. Article  Google Scholar  * Pepose JS, Gardner KM, Nestor MS, Foos RY, Pettit Th . Detection of HLA class I and II antigens in rejected

human corneal allografts. _Ophthalmology_ 1985; 92: 1480–1484. Article  CAS  PubMed  Google Scholar  * Williams KA, White MA, Ash JK, Coster DJ . Leukocytes in the graft bed associated with

corneal graft failure. Analysis by immunohistology and actuarial graft survival. _Ophthalmology_ 1989; 96: 38–44. Article  CAS  PubMed  Google Scholar  * Katami M, Madden PW, White DJ,

Watson PG, Kamada N . The extent of immunological privilege of orthotopic corneal grafts in the inbred rat. _Transplantation_ 1989; 41: 371–376. Article  Google Scholar  * Egan RM, Yorkey C,

Black R, Loh WK, Stevens JL, Woodward JG . Peptide-specific T cell clonal expansion _in vivo_ following immunization in the eye, an immune-privileged site. _J Immunol_ 1996; 157: 2262–2271.

CAS  PubMed  Google Scholar  * Yamagami S, Dana MR . The critical role of lymph nodes in corneal alloimmunization and graft rejection. _Invest Ophthalmol Vis Sci_ 2001; 42: 1293–1298. CAS 

PubMed  Google Scholar  * Tuft SJ, Coster DJ . The corneal endothelium. _Eye_ 1990; 4: 389–424. Article  PubMed  Google Scholar  * The Collaborative Corneal Transplantation Studies Research

Group. The collaborative corneal transplantation studies (CCTS). Effectiveness of histocompatibility matchin in high-risk corneal transplantation. _Arch Ophthalmol_ 1992; 110: 1392–1403. *

Gore SM, Vail A, Bradley VA, Rogers CA, Easty DL, Armitage WJ . HLA-DR matching in corneal transplantation. Systemic review of published evidence Corneal. Transplant Follow-up Study

Collaborators. _Transplantation_ 1995; 60: 1033–1039. Article  CAS  PubMed  Google Scholar  * Batchelor JR, Casey TA, Werb A, Gibbs DC, Prasad SS, Lloyd DF _et al_. HLA matching and corneal

grafting. _Lancet_ 1976; 1: 551–554. Article  CAS  PubMed  Google Scholar  * Volker-Dieben HJ, Kok-van Alphen CC, Lansbergen Q, Persijn GG . The effect of prospective HLA-A and -B matching

and corneal graft survival. _Acta Ophthalmol (Copenhagen)_ 1982; 60: 203–212. Article  CAS  Google Scholar  * Foulks GN, Sanfilippo FP, Locascio III JA, MacQueen JM, Dawson DV .

Histocompatibility testing for keratoplasty in high-risk patients. _Ophthalmology_ 1983; 90: 230–244. Article  Google Scholar  * Sanfilippo F, MacQueen JM, Vaughn WK, Foulks GN . Reduced

graft rejection with good HLA-A and B matching in high-risk corneal transplantation. _N Engl J Med_ 1986; 315: 29–35. Article  CAS  PubMed  Google Scholar  * Hoffman F, von Keyserlingk HJ,

Wiederholt M . Importance of HLA DR matching for corneal transplantation in high-risk cases. _Cornea_ 1986; 5: 139–143. Article  Google Scholar  * Baggesen K, Lamm LU, Ehlers N . Significant

effect of high-resolution HLA-DRB1 matching in high-risk corneal transplantation. _Transplantation_ 1996; 62: 1273–1277. Article  CAS  PubMed  Google Scholar  * Munkhbat B, Hagihara M, Sato

T, Tsuchida F, Sato K, Shimazaki J _et al_. Association between HLA-DPB1 matching and 1-year rejection-free graft survival in high-risk corneal transplantation. _Transplantation_ 1997; 63:

1011–1016. Article  CAS  PubMed  Google Scholar  * Vail A, Gore SM, Bradley BA, Easty DL, Rogers CA, Armitage WJ . Influence of donor and histocompatibility factors on corneal graft outcome.

_Transplantation_ 1994; 58: 1210–1216. CAS  PubMed  Google Scholar  * Hill JC . Systemic cyclosporin in high-risk keratoplasty: short _versus_ long term therapy. _Ophthalmology_ 1994; 101:

128–133. Article  CAS  PubMed  Google Scholar  * Hill JC . Systemic cyclosporin in high-risk keratoplasty: long term results. _Eye_ 1995; 9: 422–428. Article  PubMed  Google Scholar  *

Denton MD, Magee CC, Sayegh MH . Immunosuppressive strategies in transplantation. _Lancet_ 1999; 353: 1083–1091. Article  CAS  PubMed  Google Scholar  * Hill JC, Maske R, Watson P .

Corticosteroids in corneal graft rejection: oral _versus_ single pulse therapy. _Ophthalmology_ 1991; 98: 329–333. Article  CAS  PubMed  Google Scholar  * Ippoliti G, Fronterre A . Use of

locally injected anti-T monoclonal antibodies in the treatment of acute corneal graft rejection. _Transplant Proc_ 1987; 19: 2579–2580. CAS  PubMed  Google Scholar  * Ippoliti G, Fronterre A

. Usefulness of CD3 or CD6 anti-T monoclonal antibodies in the treatment of acute corneal graft rejection. _Transplant Proc_ 1989; 21: 3133–3134. CAS  PubMed  Google Scholar  * Newman DK,

Isaacs JD, Watson PG, Meyer PA, Hale G, Waldmann H . Prevention of immune-mediated corneal graft destruction with the anti-lymphocyte monoclonal antibody, CAMPATH-1H. _Eye_ 1995; 9: 564–569.

Article  PubMed  Google Scholar  * Dick AD, Meyer P, James T, Forrester JV, Hale G, Waldmann H _et al_. Campath-1H therapy in refractory ocular inflammatory disease. _Br J Ophthalmol_ 2000;

84: 107–109. Article  CAS  PubMed  PubMed Central  Google Scholar  * Schmitz K, Hitzer S, Behrens-Baumann W . Immune suppression by combination therapy with basiliximab and cyclosporin in

high risk keratoplasty. A pilot study. _Ophthalmologe_ 2002; 99: 38–45. Article  CAS  PubMed  Google Scholar  * Thiel MA, Coster DJ, Standfield SD _et al_. Penetration of engineered antibody

fragments into the eye. _Clin Exp Immunol_ 2002; 128: 67–74. Article  CAS  PubMed  PubMed Central  Google Scholar  * Klebe S, Sykes P, Coster D, Krishnan R, Williams K . Prolongation of

sheep corneal allograft survival by transfer of the gene encoding ovine interleukin 10 to donor corneal endothelium. _Transplantation_ 2001; 15: 1214–1220. Article  Google Scholar  Download

references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Flinders Drive, Bedford Park, South Australia, Australia D J Coster & K A Williams Authors * D J Coster View author publications

You can also search for this author inPubMed Google Scholar * K A Williams View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR

Correspondence to D J Coster. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Coster, D., Williams, K. Management of high-risk corneal grafts. _Eye_ 17,

996–1002 (2003). https://doi.org/10.1038/sj.eye.6700634 Download citation * Received: 28 February 2003 * Accepted: 28 February 2003 * Published: 20 November 2003 * Issue Date: 01 November

2003 * DOI: https://doi.org/10.1038/sj.eye.6700634 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link

is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * high-risk corneal transplantation * HLA matching

* immunosuppression * antibody engineering * gene therapy