**6. Treatment of corneal graft rejection**

## **6.1 Provide a healthy ocular surface**

A smooth ocular surface can be achieved through intensive and frequent non-preserved tear supplements or hyaluronate eye drops [67]. Frequent drops using non-preserved tears is necessary for managing accumulated inflammatory cytokines. Hyaluronate eye drops have been reported to be effective in managing patients with ocular surface disorders through improving the corneal epithelial barrier function, promoting corneal wound healing, and reducing ocular surface tissue damage as well as minimizing the inflammation process in DED [68].

Epithelial rejection occurred at the first three months after surgery can be seen as a linear opacification at the cornea surface which stains with fluorescein. Although the dead epithelial cells are replaced rapidly by recipient epithelial cells, it is important to remember that these recipient epithelial cells have been sensitized by the donor which can progress to deeper rejection such as stromal or endothelial rejection in the future. It can be seen as a nummular infiltrate if the rejection reaches the stroma. However, endothelial rejection can be shown as keratic precipitates where the inflammatory cells adhere to the endothelial graft [69].

#### **6.2 Immunosuppressive agents**

Topical steroid eye drops such as dexamethasone 0.1% or prednisolone acetate 1% are given every three hours per day for the first 2–3 months, then tapered gradually until it reaches zero in one year. These steroid drop regimens are different for each center. The purpose of steroid drops is to prevent and reverse any rejection episodes and avoid more endothelial cell loss. Lack of detecting signs of rejection will postpone graft treatment initiation. Delay in diagnosing or treating rejection will reduce graft sensitivity towards the treatment and may develop to an irreversible rejection [70, 71].

#### **6.3 HLA matching**

HLA matching is shown to be effective in predicting graft survival rates in a vascularized organ allotransplantation. However, the benefits from tissue matching in cornea transplantation are still debatable since the cornea has its own immune privilege as a non-vascularized tissue. Nevertheless, it was found that an active graft rejection is related to the donor HLA class I specific cytotoxic T cells.

The greater number of mismatches between HLA-A and HLA-B shows a higher risk of corneal tissue developing into graft rejection. These tissue mismatches are considered as a high-risk factor for rejection after corneal transplantation [72–76]. Whilst Collaborative Corneal Transplantation Studies (CCTS) suggest the necessity of HLA matching in corneal transplantation remains doubtful, it may be useful for high-risk patients although it is still not considered to do the tissue matching as part of routine preoperative assessment due to the donor cornea tissue available [77].

Minor histocompatibility antigens such as ABO blood antigens are a different class of cell surface proteins that are also expressed by the corneal epithelium. It

is coded throughout the genome at various loci [78]. CCTS concluded with ABO blood matching, the possibility for someone having graft rejection is 41% if the ABO antigens are incompatible and 31% may experience rejection for the compatible ABO antigens. The study concluded ABO matching may still be considered useful in predicting corneal graft rejection. However, doing HLA matching is still debatable - not only because of the lack in the availability of cornea tissue globally but also its very expensive [79].

#### **7. Conclusion and future prospects**

Cornea graft survival rates are influenced by many factors. Dry eye as part of ocular surface disorders is one important thing that we should care for. The aim for dry eye or OSD management is to treat the hyperosmolarity condition of the tear film to reduce the expression of a response from our immune system to any foreign antigens from desiccating stress or inflammation. Although the cornea has immune privilege due to being avascular and lymph node free, a successful prevention of immune rejection is better compared to immune suppression by immune modifying treatments such as gene therapy post transplantation. Minor histocompatibility complex tissue matching can be done due to its low cost. However, ABO antigens testing is not as specific as major histocompatibility tests.

Cornea as the only organ that has its own immune privilege is still in doubt for testing major histocompatibility complex tissue matching. Mainly, because most of major histocompatibility testing only work for class II but not shown effective for class I. Unfortunately, due to human major histocompatibility complex genes are highly polymorphic, any random allocation of HLA will achieve the required matching level in a very long time which are very unethical for our patients. If in the future, there will be a HLA matching that is highly specific, low cost and only needs a period of time to get the test result, probably the HLA testing can be applied as a routine evaluation to provide higher number of graft survival in the future.

As mentioned in the literature, a high-risk condition such as corneal vascularization, DED and prolonged use of antiglaucoma medication can reduce the corneal graft survival rate. Therefore, the application of anti VEGF through injection on the subconjunctival, an adjunct non-preservative topical lubricant in glaucoma medication and the use of lifitegrast as the antagonist of LFA-1 and inhibits T cell formation in dry eye management will probably useful and create a promising result related to a higher graft survival rate in the future.

To conclude, a prospective clinical trial to investigate the role of preexisting DED in the context of corneal transplantation and its influence on graft survival is needed. Understanding the role of HLA in corneal graft rejection from an immunological point of view as well as the necessity of conducting a comprehensive knowledge of the HLA tissue matching will create other options to prevent graft rejection. Future pharmacotherapies for DED with novel targets are the focus of ongoing research, and several promising treatment options are expected.

#### **Acknowledgements**

The author would like to thank Professor John S. Jarstad, MD, FAAO, FRSM UK(oph), Professor of Clinical Ophthalmology Comprehensive, Cataract & Refractive Surgery, Department of Ophthalmology, Tampa for his contribution in English language editing.

*How Ocular Surface Disorder Affected Corneal Graft Survival DOI: http://dx.doi.org/10.5772/intechopen.98480*
