Pancreatic Islet Transplantation to the Anterior Chamber of the Eye

Type 1 diabetes (T1D) is caused by the destruction of pancreatic islet cells through an autoimmune attack against insulin-producing beta cells in the endocrine pancreas. This in turn impairs glucose control causing multi-organ failure, morbidity and mortality which are also associated with high economic costs. While strict glucose control with insulin replacement therapy is the standard-of-care, achieving controlled glucose homeostasis remains a major challenge. Replacement of the insulin-producing beta cells through pancreatic islet transplantation has emerged as a promising therapy for T1D. Thus far, hundreds of islet transplantations have been performed in ongoing clinical trials worldwide. Islet transplantation is on the verge of obtaining FDA approval as a standard therapy in T1D. While ongoing clinical trials have focused on islet transplantation into the hepatic portal system, the search for alternative islet transplantation sites remains a priority for funding agencies and an active area of research. Studies have explored islet transplantation into different locations. One location of interest is the anterior chamber of the eye (ACE).

Importantly, these studies have shown several advantages offered by islet transplantation into the anterior chamber of the eye compared to other sites, which include:

• Local/topical immunosuppression and intervention potentially feasible.
• No IBMIR (Instant Blood Mediated Inflammatory Reaction) as when islets are injected to the portal vein with a major loss of islets.
• Good survival of transplanted islets due to limited anoxia time (fewer islets required to improve glycaemic control compared to other islet transplantation sites (i.e., liver)).
• Non-invasive monitoring/assessment of grafted islets with potential cellular resolution.
• Intraocular islets may function as "reporters" of native islets or islets transplanted elsewhere.
• Simpler surgical procedure as compared to other islet transplantation sites (i.e., liver).

Access to the ACE is a safe procedure routinely used by ophthalmic surgeons for the anterior segment surgery (e.g. cataract operations) and extraction of intraocular fluid for diagnostic purposes. Importantly, the ACE has unique immunological properties which regulate the immune system in such a way that allogeneic tissue placed in this compartment may be protected from immune rejection and this correlates with the generation of systemic immune tolerance through anterior chamber-associated immune deviation (ACAID) (Niederkorn and Streilein, 1982; Streilein and Niederkorn, 1985). Hence, the potential of inducing systemic immune tolerance and eliminating severe side-effects associated with systemic immunosuppression through local/topical drug application further highlight the significance and clinical relevance of this approach. Moreover, this introduces the possibility of transplanting additional islets elsewhere in the body without risk of rejection. Importantly, it was recently shown that islet grafts in the ACE also serve as "reporters" for the status of the pancreatic islets (Ilegems et al., 2013). This essentially demonstrates that islets in the ACE are reliable, easily accessible reporters for the overall health and islet function during interventions regimens aimed at regulating different aspects of the pancreatic islets.

INTERVENTION AND INDICATION