In type 1 diabetes, an autoimmune response attacks the pancreas’ insulin-producing beta cells, leading to significant fluctuations in blood sugar levels. Lifelong daily insulin treatments are standard for patients, but replacing lost beta cells with islet transplantation, a group of cells in the pancreas, is an attractive option. However, this strategy requires patients to take lifelong immunosuppressive drugs to prevent rejection. To address this shortcoming, a team at Massachusetts General Hospital (MGH) and Harvard Medical School collaborated with researchers at the Georgia Institute of Technology and the University of Missouri to develop a new biomaterial that, when mixed with islands, makes it possible for islands to survive after transplantation without the need for long-term immunosuppression.
In a preclinical study performed at MGH and published in The progress of science, the researchers tested the biomaterial – which includes a new protein called SA – FasL that promotes immune tolerance and is attached to the surface of microgel beads – in a non-human primate model of type 1 diabetes. The material was mixed with islets and then transplanted into a bioconstructed sac formed by the omentum – a fold of adipose tissue that hangs from the stomach and covers the intestines. After transplantation, the animals received a single anti-rejection drug (rapamycin) for three months.
“Our strategy of creating a local immune-privileged environment enabled islands to survive without prolonged immunosuppression and achieved robust blood glucose control in all diabetic non-human primates during a six-month study period,” said lead author Ji Lei, MD, MBA. an associate immunologist at MGH and an assistant professor of surgery at Harvard Medical School. “We believe that our approach allows transplants to survive and control diabetes for much longer than six months without anti-rejection drugs because surgical removal of the transplanted tissue at the end of the study resulted in all animals returning immediately to a diabetic state.”
Lei, who is also head of the Human Islet / Cell Processing Special Service cGMP Facility at MGH, notes that transplantation of islets to the omentum has several advantages over the current clinical method of transplantation into the liver. “Unlike the liver, the omentum is a non-vital organ that allows it to be removed should unwanted complications occur,” he explains. “Thus, omentum is a safer site for transplants to treat diabetes and may be particularly well suited for stem cell-derived beta cells and bioconstructed cells.”
Co-author James F. Markmann, MD, PhD, Head of the Department of Transplant Surgery and Head of Clinical Operations at the Transplant Center at MGH, emphasizes that the study of non-human primates is a highly relevant preclinical animal model. “This localized immunomodulatory strategy succeeded without long-term immunosuppression and shows great potential for application in type 1 diabetes patients,” he says.
A clinical trial is planned based on the researchers’ results.
Additional study authors include María M. Coronel, Esma S. Yolcu, Hongping Deng, Orlando Grimany-Nuno, Michael D. Hunckler, 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.