Pitt Team Makes Important Step Toward Xenotransplantation to Treat Type 1 Diabetes

For the first time, scientists have achieved survival of islet cells and normal glucose regulation without diet restrictions or insulin injections in a diabetic nonhuman primate for longer than one year, according to a team at the University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC, and the Thomas E. Starzl Transplantation Institute. Their results are published in the December issue of the American Journal of Transplantation.

The findings, involving genetically altered islet cells from donor pigs, are an important step toward the potential clinical application of islet cell xenotransplantation, according to senior author Massimo Trucco, Hillman Professor of Pediatric Immunology in Pitt’s School of Medicine and director of the Division of Immunogenetics at Children’s Hospital. The islet cells were isolated from genetically altered pigs produced by Revivicor Inc., a Blacksburg, Va.-based regenerative medicine company. The company, of which UPMC is a shareholder, is a longtime collaborator of Trucco. Islet cells from these pigs contain a gene that produces the human version of a cell surface protein called CD46, which plays a key role in modulating an immunological pathway that leads to immediate rejection of foreign cells.

Human islet cell transplantation has been performed for about a decade to treat patients with type 1 diabetes, in which the body’s own immune system destroys the insulin-producing beta cells (a type of islet cell) of the pancreas. Patients with type 1 diabetes must take insulin every day to live, and the vast majority of those who have received islet cell transplants have been forced to return to insulin injections because the transplanted cells lose function within months, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

“Until now, long-term survival of transplanted pig islet cells has not been achieved, clinically or in the laboratory, without significant rejection and other issues,” Trucco said. “Now, we have been able to achieve functionality of transplanted cells, and complete reversal of diabetes, for longer than one year in a monkey.”

In the study, Trucco and colleagues isolated the genetically altered pig pancreas cells and then transplanted them into several monkeys with diabetes by infusion into a large liver vein.

Sufficient numbers of the infused cells survived, resulting in correction of blood glucose levels—without the use of insulin or diet modification—for longer than three months in four out of five subjects. One monkey was followed for more than one year and maintained normal blood-sugar levels.

The gene manipulation of the cells transplanted by Trucco’s team also may have influenced the antibody-driven rejection response to foreign cells, which reduced the need for immunosuppression to preserve a sufficient mass of islet cells for glucose control over the long term.

The potential use of donor cells from pigs in human islet cell transplantation also solves another hurdle, namely the lack of pancreases available for transplant, according to Trucco.