In type 1 diabetes, an autoimmune response attacks the insulin-producing beta cells of the pancreas, causing dramatic fluctuations in blood sugar levels. Lifelong daily insulin therapy is the standard of care for patients, but replacement of lost beta cells by transplanting islets (a group of cells in the pancreas) is an attractive option. However, this strategy requires patients to take immunosuppressive drugs for life to prevent rejection. To address this shortcoming, a team from Massachusetts General Hospital (MGH) and Harvard Medical School, in collaboration with researchers at Georgia Tech and the University of Missouri, has developed a novel biomaterial that, when mixed with pancreatic islets, allows islets to survive transplants. Post-survival does not require long-term immunosuppression.
Conducted at MGH and published in scientific progress, the researchers tested biomaterials in a non-human primate model of type 1 diabetes — including a novel protein called SA-FasL that promotes immune tolerance and is tethered to the surface of microgel beads . The material is mixed with pancreatic islets and then transplanted into a bioengineered bag formed by the omentum — a fold of fatty tissue that hangs down from the stomach and covers the gut. After transplantation, animals received a single anti-rejection drug (rapamycin) for three months.
“Our strategy of creating a local immune privileged environment enabled islets to survive without long-term immunosuppression and achieved robust glycemic control in all non-human primates with diabetes over the six-month study period, said lead author Ji Lei, MD, MBA, associate immunologist at MGH and assistant professor of surgery at Harvard Medical School. “We believe that our approach allowed grafts to survive and control diabetes for more than six months without anti-rejection drugs, as surgical removal of the grafted tissue at the end of the study resulted in a rapid return to diabetic status in all animals.”
Lei, who is also director of the special services cGMP facility for human islet/cell processing at MGH, noted that transplanting islets into the omentum has several advantages over the current clinical approach of transplanting into the liver. “Unlike the liver, the omentum is a non-vital organ that can be removed if undesired complications arise,” he explained. “Thus, the omentum is a safer location for transplantation to treat diabetes and may be particularly suitable for stem cell-derived beta cells and bioengineered cells.”
Co-corresponding author, MD, MD, Director of Transplant Surgery and Director of Clinical Operations at the MGH Transplant Center, emphasized that non-human primate studies are a highly relevant preclinical animal model. “This local immunomodulation strategy has been successful in the absence of long-term immunosuppression and shows great potential for application in patients with type 1 diabetes,” he said.
Based on the researchers’ results, a clinical trial is being planned.
Additional study authors include María M. Coronel, Esma S. Yolcu, Hongping Deng, Orlando Grimany-Nuno, Michael D. Hunkler, Vahap Ulker, Zhihong Yang, Kang M. Lee, Alexander Zhang, Hao Luo, Cole W. Peters, Zhongliang Zou, Tao Chen, Zhenjuan Wang, Colleen S. McCoy, Ivy A. Rosales, Haval Shirwan and Andrés J. García.
This work was supported by the Juvenile Diabetes Research Foundation, the National Institutes of Health, and the National Science Foundation.