Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate

Abstract

Replacement of the insulin-secreting beta cells through transplantation of pancreatic islets to the liver is a promising treatment for type-1 diabetes. However, low oxygen tension, shear stress, and the induction of inflammation lead to significant islet dysfunction and loss. The anterior chamber of the eye (ACE) has gained considerable interest and represents an alternative therapeutic islet transplantation site because of its accessibility, high oxygen tension, and immune-privileged milieu. We have previously demonstrated the feasibility of intraocular islet transplant in mouse and nonhuman primate models of type-1 diabetes and are now assessing its efficacy on glucose homeostasis in a nonhuman primate model of type-2 diabetes. We transplanted allogeneic donor islets (1,500 islet equivalents/kg) into the anterior chamber of one eye in a cynomolgus monkey with high-fat-diet-induced type-2 diabetes. Repeated examinations of the anterior and posterior segments of both eyes were done to monitor the engrafted islets and assess the overall ocular health. Fasting blood glucose level, blood biochemistry, and other metabolic parameters were routinely evaluated to determine the function of the islet graft and diabetes status. The transplanted islets were rapidly engrafted onto the iris and became vascularized 1 month after transplantation. We did not detect changes in intraocular pressure, cataract formation, ophthalmitis, or retinal vessel deformation. A significant lower fasting blood glucose level was observed while the graft was in place, and the transplantation reverts the progression of diabetes. The metabolic markers, hemoglobin A1C and fructosamine, demonstrated improvement following islet transplantation. As a conclusion, intraocular islet transplantation in one eye of a cynomolgus monkey with type-2 diabetes improved its overall plasma glucose homeostasis, as evidenced by short-term measures and long-term metabolic markers. These results further support the future application of the ACE as an alternative site for clinical islet transplants in the context of type-2 diabetes.

Challenges in stem cell-derived islet replacement therapy can be overcome

“…Moreover, our studies demonstrated immunosuppressionfree, long-term survival of intraocular islet allografts in mouse and nonhuman primate models 27,28 . These studies provided evidence for local and peripheral immune regulation consistent with donor-specific tolerance that promoted the survival of additional islet grafts from the same donors 27 .…”

Local Dexamethasone Administration Delays Allogeneic Islet Graft Rejection in the Anterior Chamber of the Eye of Non-Human Primates

“…The transduced islets were verified under a fluorescence microscope (SP8, Leica, Germany) for EGFP fluorescence before transplantation. A small self-sealing incision was made on the clear cornea, 3 mm away from the cornea-sclera junction, and around 50 islets were transplanted into the ACE of each monkey as previously described 8 . A 0.5 ml bolus dose of sub-conjunctival dexamethasone (4 mg/ml; DBL, Pfizer, New York, USA) injection was given immediately after the transplantation.…”

Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes

“…Because of this, the ACE can be used to monitor auto-immune response in islet cells, while simultaneously monitoring the morphology of transplanted islet. A study by Tun et al demonstrated that total of 12,000 islets (1500 IEQ/kg) transplantation in a left eye site in cynomolgus monkeys induced with early T2D through a high fat diet was able to delay progression of T2D and related complications (72). The authors observed that three months after immunosuppressants were withdrawn, the primates were still able to control hyperglycemia, indicating an acquired immune privilege/tolerant status for the transplanted islets.…”