The Impact of Donor Diabetes on Corneal Immune Cells and Graft Survival

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Corneal transplantation is the most commonly performed allografting procedure in the world—nearly 40,000 cases in the United States and over 200,000 globally are performed each year. As surgical techniques, eye banking procedures and prophylactic measures against graft rejection have improved, the field has also become more sensitized to the quality of the donor tissue, including donor factors that can impact long-term graft survival. In this regard, and in the context of the global `epidemic' of diabetes which affects over 10% of the American population (over 30 million people), there are increasing reports that the diabetic status of donors can adversely impact corneal graft survival. While the diabetic state in graft recipients, which is associated with delayed healing and prolonged inflammation, has long been identified as a risk factor for transplant longevity, the concept that a history of diabetes in the tissue donor can also impact graft survival is both novel and potentially highly impactful from an eye banking and tissue selection standpoint. This would mean that corneal transplant risk stratification would include the donor diabetic state in the decision algorithm for tissue allocation. To investigate the potential role of the donor diabetic state on graft immunity, we began preliminary studies in a mouse model of diabetes to assess how it would affect the resident immune cells of the cornea, which could impact host sensitization and alloimmunity. Our preliminary data show that (1) there are more matured corneal resident antigen-presenting cells (APC) in diabetic mice, (2) both penetrating and lamellar (DSEK) allografts procured from diabetic donor mice have significantly worse survival than those procured from non-diabetic donors, (3) hosts receiving diabetic tissue show heightened T helper-1 (Th1) immunity to donor-derived antigens. Moreover, our preliminary data suggest that (4) glycemic control in diabetics decreases MHC-II expression by corneal APC. Accordingly, we hypothesize that the diabetic state induces an altered corneal microenvironment that alters the immune homeostasis of the cornea, inducing APC maturation and regulatory T cell dysfyunction, that lead to heightened host sensitization and graft rejection. To test this hypothesis, we will pursue three specific aims. In Aim 1, we will define the degree of change in corneal APC functional phenotype in diabetic mice and assess the alloimmune response in hosts receiving diabetic donor tissue (PK and DSEK). We will then investigate the mechanisms by which graft- derived APC from diabetic donors impact host allosensitization (Aim 2) and regulatory T cell (Treg) dysfunction (Aim 3). This grant, which represents a new area of investigation, is anchored in the core expertise of our lab, which has studied corneal transplant immunity for more than 25 years. Knowledge gained from this grant holds the potential to impact eye banking and tissue allocation as well as open new translational venues such as manipulating donor tissue APC maturation/activation ex vivo, improving transplant outcomes and reducing the risk of donor tissue shortages as a result of excluding all diabetic tissues.