Mechanisms of Corneal Graft Rejection

Abstract

The history of corneal transplantation reaches back over 150 years. Kissam performed one of the first penetrating keratoplasties when he transplanted a pig cornea onto a human in 1838. Only two interrupted sutures were used, and the surgery was performed without anesthesia! In retrospect, no one would be surprised to learn that the porcine corneal xenograft was rejected. Thirty years later, May transplanted rabbit corneal grafts to humans, but concluded that the failures in the first 24 attempts were the result of "imperfect technique and the inability to keep the eyes properly bandaged." The first documented report of a successful penetrating keratoplasty in a human subject was performed by Zirm in 1905. As we enter the new millennium, corneal transplantation remains the oldest, most common, and, arguably, the most successful form of solid tissue transplantation. In the United States alone, approximately 36,000 corneal transplants are performed each year. The success rate for corneal transplants is in excess of 90% in uncomplicated cases, even though HLA tissue typing is not performed and systemic immunosuppressive drugs are not administered. In spite of this extraordinary success, immune rejection remains the leading cause of corneal graft failure. Many inferences about the immunobiology of corneal graft rejection have been based on clinical observations; however, confirmation of these hypotheses requires prospective studies under controlled settings. The prudent use of animal models has fostered analytic studies on the immunobiology of corneal allografts without the complicating and confounding effects of topical steroids that are typically used on most keratoplasty patients. Although animal models of penetrating keratoplasty have been in use for almost a half-century, until recently, progress in understanding the immune mechanisms of corneal graft rejection has been slow. However, the widespread use of rodent models of orthotopic corneal transplantation has shed new light on the pathogenesis of corneal graft rejection.

Superficial Hypertrophic Dendriform Epitheliopathy

“…3Y7 SHDE, in particular, represents an entity whose etiology is poorly understood and can lead to long-term compromise of the corneal graft. 1 Previous studies have demonstrated that postkeratoplasty surface keratopathy has a variable range of occurrence from 33% to 76% in patients after penetrating keratoplasty. 8,9 Although much attention is given to immune graft rejection, surface disease is a more common problem after keratoplasty and remains a leading cause of graft failure.…”

“…1 The ocular surface is of vital importance to the success of the corneal graft, and maintenance of the surface postoperatively is arguably one of the most important components of management after surgery. Breakdown of the ocular surface after keratoplasty degrades visual function and increases the risk of functional graft failure through a variety of mechanisms, including infection, scarring, vascularization, thinning, and perforation.…”

Corneal Allograft Rejection: Immunopathogenesis to Therapeutics

“…MHC-II antigens are more selectively expressed, and are limited to the cell surface of immunocompetent antigen-presenting cells (APCs) such as DCs, macrophages and Langerhans cells [18,19]. These MHC antigens are expressed by HLA-DQ, -DR and –DW genes in humans and are not constitutively expressed in the center of an otherwise healthy cornea [20]. Foreign antigens are presented to naïve T cells by APCs as processed peptides in the presence of MHC-II and co-stimulatory molecules to program recognition of “non-self” antigens.…”

Cornea: Window to Ocular Immunology

“…However, subsequent studies have clearly shown that MHC class I molecules are expressed on all three layers of the cornea, although the density of these molecules is extraordinarily low on the corneal endothelium [9, 10, 14, 15]. By contrast, MHC class II molecules are not constitutively expressed on any cells within the cornea [9, 10, 14, 15]. The cornea expresses multiple minor histocompatibility molecules including the male-specific H-Y antigen [13, 16-18].…”

“…The severity of HSV stromal keratitis is correlated with the intensity of DTH responses to HSV-1 antigens and the density of corneal antigen-presenting Langerhans cells (LC) [82-85]. The absence of MHC class II positive LC in the central corneal epithelum plays an important role in reducing the immunogenicity of corneal allografts and in supporting immune privilege of the ocular surface [11, 14, 15, 30, 54]. Corneal LC are crucial for the induction of HSV-specific CD4 + T cell responses and the generation of corneal lesions in HSV stromal keratitis [84].…”