Diabetes Research Institute
University of Miami Miller School of Medicine
Islet transplantation in the immune privileged eye anterior chamber and immune tolerance induction to treat T1D
Alexander Shishido1, Christopher Martin1, Midhat Abdulreda1.
1Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
Beta-cell replacement therapy through pancreatic islet transplantation re-establishes glycemic control and hypoglycemia awareness. This improves significantly the quality of life of islet transplant recipients. While islet transplantation in the liver is on the verge of obtaining FDA approval, it has become evident that inflammatory and immunological host responses associated with the liver lead to limited graft efficacy and survival. Therefore, several alternatives sites such as the omentum and intramuscular islet transplantation have been proposed. We on the other hand have previously reported in pre-clinical rodent and non-human primate models that the anterior chamber of the eye (ACE) offers a viable islet transplant site with several technical and functional advantages. Intraocular transplantation is minimally invasive comparable to routine injection through the cornea. Islets in the ACE can be monitored noninvasively and longitudinally in real-time. Importantly, the ACE is also endowed with immune privilege which favors long-term survival of intraocular islet allografts without life-long immune suppression. Our recent results also show that intraocular islet transplant also offers the potential to induce systemic/peripheral immune tolerance, whereby, islet allografts survived long-term under the kidney capsule of recipients with previously “tolerated” intraocular islet allografts from the same donor. In these studies, we transplanted ~10 DBA/2 (H-2d) islets into the ACE of streptozotocin (STZ)-diabetic B6 (H-2b) recipients that were treated with anti-CD154 (MR-1; 500 µg/day) on days -1, 0, 3, and 7 of transplantation. Survival of islet allografts in the ACE was monitored with noninvasive intravital imaging and mice with “tolerated” islets received a 2nd transplant of 500 – 700 DBA/2 islets under the kidney capsule, and survival of islet grafts in the kidney was assessed based on glycemia without sustained immune suppression. Longitudinal monitoring of the islet allografts in the ACE and under the kidney capsule showed significantly prolonged survival of both grafts without sustained immune suppression. Importantly, these findings demonstrate the potential for peripheral immune tolerance induction through intraocular transplantation to accomplish sustained survival and function of transplanted pancreatic islets without life-long immunosuppression.
This work was funded in part by the Diabetes Research Institute Foundation and NIH/NIDDK.
11:00 - 12:30
|Islet Immunity and Tolerance||Islet transplantation in the immune privileged eye anterior chamber and immune tolerance induction to treat T1D||Plenary Room 1|