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CORNEAL GRAFT REACTIONS (  Figure 16-9)

Blindness due to opacity or distortion of the central portion of the cornea is a remediable disease. If all other structures of the eye are intact, a patient whose vision is impaired solely by corneal opacity can expect great improvement from a graft of clear cornea into the diseased area (see Chapter 6). Trauma, including chemical burns, is one of the most common causes of central corneal opacity. Others include scars from herpetic keratitis, endothelial cell dysfunction with chronic corneal edema (including pseudophakic bullous keratopathy and Fuchs's dystrophy), keratoconus, and opacities from previous graft failures. All of these conditions represent indications for penetrating corneal grafts, provided the patient's eye is no longer inflamed and the opacity has been allowed maximal time to undergo spontaneous resolution (usually 6-12 months). It is estimated that approximately 10,000 corneal grafts are performed in the USA annually. Of these, about 90% can be expected to produce a beneficial result.

The cornea was one of the first human tissues to be successfully grafted. The fact that recipients of corneal grafts generally tolerate them well can be attributed to (1) the absence of blood vessels or lymphatics in the normal cornea, (2) the lack of presensitization to tissue-specific antigens in most recipients, and (3) anterior chamber acquired immune deviation (ACAID). This is a series of unique immunologic properties of the anterior chamber, conferring on the graft area the status of immune privilege. Reactions to corneal grafts do occur, however, particularly in individuals whose own corneas have been damaged by previous inflammatory disease. Such corneas may have developed both lymphatics and blood vessels, providing afferent and efferent channels for immunologic reactions in the engrafted cornea.

Although attempts have been made to transplant corneas from other species into human eyes (xenografts), particularly in countries where human material is not available for religious reasons, most corneal grafts have been taken from human eyes (allografts). Except in the case of identical twins, such grafts always represent the implantation of foreign tissue into a donor site; thus, the chance for a graft rejection due to an immune response to foreign antigens is virtually always present.

The cornea is a three-layered structure composed of a surface epithelium, an oligocellular collagenous stroma, and a single-layered endothelium. Although the surface epithelium may be sloughed and later replaced by the recipient's epithelium, certain elements of the stroma and all of the donor's endothelium remain in place for the rest of the patient's life. This has been firmly established by sex chromosome markers in corneal cells when donor and recipient were of opposite sexes. The endothelium must remain healthy in order for the cornea to remain transparent, and an energy-dependent pump mechanism is required to keep the cornea from swelling with water. Since the recipient's endothelium is in most cases diseased, the central corneal endothelium must be replaced by healthy donor tissue.

A number of foreign elements exist in corneal grafts that might stimulate the immune system of the host to reject this tissue. In addition to those mentioned above, the corneal stroma is regularly perfused with IgG and serum albumin from the donor, although none of the other blood proteins are present-or only small amounts. While these serum proteins of donor origin rapidly diffuse into the recipient stroma and are thus removed from the graft site, they are theoretically immunogenic.

HLA incompatibility between donor and recipient has been shown by several authors to be significant in determining graft survival, particularly when the corneal bed is vascularized. It is known that most cells of the body possess these HLA antigens, including the endothelial cells of the corneal graft as well as certain stromal cells (keratocytes). The epithelium has been shown to possess a non-HLA antigen that diffuses into the anterior third of the stroma. Thus, while much foreign antigen may be eliminated by purposeful removal of the epithelium at the time of grafting, that amount of antigen which has already diffused into the stroma is automatically carried over into the recipient.

Despite numerous analytic studies supporting the role of HLA incompatibility in corneal graft rejection, a recent multicenter clinical trial found no use in HLA typing high risk grafts. In this study, ABO blood typing did provide a slight protective effect in high-risk cases. These surprising findings are leading many investigators to restudy the role of major and minor antigens in corneal graft rejection.

Both humoral and cellular mechanisms have been implicated in corneal graft reactions. It is likely that early graft rejections (2-4 weeks from surgery) are cell-mediated reactions. Cytotoxic lymphocytes have been found in the limbal area and stroma of affected individuals, and phase microscopy in vivo has revealed an actual attack on the grafted endothelial cells by these lymphocytes. Such lymphocytes generally move inward from the periphery of the cornea, making what is known as a "rejection line" as they move centrally. The donor cornea becomes edematous as the endothelium becomes compromised by an accumulation of lymphoid cells.

Late rejection of a corneal graft may occur several weeks to many months after implantation of donor tissue into the recipient eye. Such reactions may be antibody-mediated, since cytotoxic antibodies have been isolated from the serum of patients with a history of multiple graft reactions in vascularized corneal beds. These antibody reactions are complement- dependent and attract polymorphonuclear leukocytes, which may form dense rings in the cornea at the sites of maximum deposition of immune complexes. In experimental animals, similar reactions have been produced by corneal xenografts, but the intensity of the reaction can be markedly reduced either by decomplementing the animal or by reducing its leukocyte population through mechlorethamine therapy.

Treatment

The mainstay of the treatment of corneal graft reactions is corticosteroid therapy. This medication is generally given in the form of frequently applied eye drops (eg, 1% prednisolone acetate every hour) until the clinical signs abate. These clinical signs consist of conjunctival hyperemia in the perilimbal region, a cloudy cornea, cells and protein in the anterior chamber, and keratic precipitates on the corneal endothelium. The earlier treatment is applied, the more effective it is likely to be. Some cases may require systemic or periocular corticosteroids in addition to local eye drop therapy. High-dose intravenous steroids may also be efficacious if used sooner than 8 days after onset of the rejection period. Occasionally, vascularization and opacification of the cornea occur so rapidly as to make corticosteroid therapy useless, but even the most hopeless-appearing graft reactions have occasionally been reversed by corticosteroid therapy. Oral cyclosporine has been used successfully in the treatment of corneal graft rejection, and some benefit may be derived from cyclosporine eye drops.

Patients known to have rejected many previous corneal grafts are managed somewhat differently, particularly if disease affects their only remaining eye. Some surgeons may choose to find a close HLA match between donor and recipient, but conflicting analytic studies make doing so of questionable use. Pretreatment of the recipient with immunosuppressive agents such as azathioprine has also been resorted to in some cases.

10.1036/1535-8860.ch16

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