Corneal transplantation is the oldest, most common and usually the most successful type of solid tissue allograft. The acceptancc of corneal allografts compared to other categories of allografts is called immune privilege. However, some conditions rob the corneal allograft of its immune privilege and promote rejection, which remains the leading cause of corneal graft failure. The precise immune mechanism underlying graft failure is incompletely understood. While differences in human leukocyte antigen (HLA) molecules between donor and host contribute to the alloreactivity driving the donor-antihost response, the cytokine milieu consisting of molecules that promote and regulate the alloresponse after transplantation is also critical. Single nucleotide polymorph isms (SNPs) in the promoter and coding regions of cytokine genes are associated with differential levels of expression and therefore play an important role in transplantation immunology. Cytokines are integral components of an inflammatory response and there are several potential sources of cytokine release within the cornea and the anterior chamber. This project is a candidate gene association study, focusing on genes known to be involved in ocular immune privilege and the compromise thereof, in corneal transplant recipients at increased risk of rejection (i.e., 'high risk corneal transplantation). In view of their central roles in initiation and suppression of the inflammatory response, tumour necrosis factor alpha (Tufa), interleukin - IO (IL• I 0), interleukin- 17 ( IL-1 7), thrombospondin•1 (TSP-I), vascular endothelial growth factor-A (VEG F-A) and the glucocorticoid cortisol were investigated. All transplants had three-year follow-up and results were analysed by PHASE (maximum-likelihood) analysis is to determine haplotype frequencies. Significant association between two extended TNF-u haplotypes and corneal graft outcome was found: TCTGGA was associated with a decreased risk of cornea] graft failure (n=384, RR 0.04, Cl 002-0.671, P <0.05, Pc <0.05) and TCTAGA was associated with increased risk of failure (n=384, RH. 3.59, Cl 3.21-4.03, P <0.05, Pc <0.05). In addition, a significant association was observed between the 3-1ocus TSP-] haplotype ACA, and an increased risk of corn ca I graft failure (n==359, OR 2.27, 95% Cl 1.65-3.13, P<0.05, P, <0.05).

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In vivo confocal microscopy (IVCM) offers a unique real time non-invasive imaging method to explore live tissues at cellular and subcellular levels of histological detail with magnifications very much comparable to conventional ‘ex vivo’ light microscopy. Therefore it has been widely used over the past two decades to investigate the ocular surface and cornea in health, disease and following surgical procedures. One of the main challenges in understanding IVCM is to get a proper interpretation of the images that present various figures and patterns of tissue structures all in black and white with variable degree of reflectivity, being whiter (or brighter) when they are more (or hyper) reflective. The lack of good correlation between IVCM and corresponding light microscopy for the same tissue samples has lead to speculative interpretations of IVCM images in the literature. In this work we tried to fill that gap through performing IVCM to patients with various corneal and ocular surface disorders just few days prior to obtaining the tissue samples (corneal graft, excisional biopsy or alcohol delamination) for histopathological examination to make sure that IVCM images were truly representative to the tissue details that might change if more time was left to elapse between IVCM and tissue sampling. In ocular surface disease group (chapter three) we contrasted IVCM criteria in conjunctival epithelial overgrowth onto the cornea in limbal stem cell deficiency and Pterygium-like disorders with those seen in Corneal/Conjunctival Intraepithelial neoplasia (CIN) to confirm reliable diagnostic criteria of CIN with IVCM. In corneal oedema (chapter four) IVCM viewing of (histologically confirmed) subepithelial fibroblasts without clinically visible corneal scarring has been reported for the first time in IVCM literature particularly in Fuchs endothelial dystrophy. Sub-basal corneal nerve reduction as well as stromal keratocytes and endothelial changes were clearly illustrated with IVCM. In keratoconus cases (chapter five) morphological epithelial changes related to regenerative atypia have been studied for the first time and compared to those seen in CIN through light microscopy and IVCM in addition to other epithelial changes associated with keratoconus. Novel IVCM criteria for Bowman’s zone breaks have been described and compared carefully with histological sections. In corneal dystrophies (chapter six) IVCM criteria in Thiel-Behnke’s corneal dystrophy (CDBII) as well as in macular, granular and lattice dystrophy correlated well with light microscopic findings with a novel IVCM pattern in one Macular dystrophy case. In Acanthamoeba keratitis (chapter seven) a new form of Acanthamoeba cysts has been described for the first time through IVCM. Moreover this study presented for the first time IVCM diagnostic criteria in corneal intraepithelial neoplasia, keratoconus, Acanthamoeba keratitis and some corneal dystrophies. A comprehensive IVCM illustration of various types and stages of corneal fibrosis has been achieved as well.