BOSTON – In type 1 diabetes, an autoimmune response attacks the pancreas’s insulin-producing beta cells, leading to marked fluctuations in blood sugar levels. Lifelong daily insulin treatments are standard for patients, but replacing lost beta cells through transplants of islets, a group of cells in the pancreas, represents an attractive option. This strategy requires that patients take lifelong immunosuppressive drugs to prevent rejection, however. 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 novel biomaterial that, when mixed with islets, allows islets to survive after transplant without the need for long-term immunosuppression.
In a preclinical study conducted at MGH and published in Science Advances, the researchers tested the biomaterial—which includes a novel protein called SA-FasL that promotes immune tolerance and is tethered to the surface of microgel beads—in a nonhuman primate model of type 1 diabetes. The material was mixed with islets and then transplanted to a bioengineered pouch formed by the omentum—a fold of fatty tissue that hangs from the stomach and covers the intestines. After transplantation, animals received a single anti-rejection drug (rapamycin) for three months.
“Our strategy to create a local immune-privileged environment allowed islets to survive without long-term immunosuppression and achieved robust blood glucose control in all diabetic nonhuman primates during a six-month study period,” says 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 the 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 promptly returning to a diabetic state.”
Lei, who is also director of the Human Islet/Cell Processing Special Service cGMP Facility at MGH, notes that transplanting islets to the omentum has several advantages over the current clinical approach of transplanting to the liver. “Unlike the liver, the omentum is a non-vital organ allowing its removal should undesired complications be encountered,” he explains. “Thus, the omentum is a safer location for transplants to treat diabetes and may be particularly well suited for stem-cell-derived beta cells and bio-engineered cells.”
Co-corresponding author James F. Markmann, MD, PhD, chief of the Division of Transplant Surgery and director of Clinical Operations at the Transplant Center at MGH stresses that the non-human primate study is a highly relevant pre-clinical animal model. “This localized immunomodulatory strategy succeeded without long-term immunosuppression and shows great potential for application to type 1 diabetes patients,” he says.
A clinical trial is being 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.
About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2021, Mass General was named #5 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham health care system.
FasL microgels induce immune acceptance of islet allografts in nonhuman primates
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