City of Hope researchers have found a sustainable way to treat late-stage type 1 diabetes that may enable patients to make their own insulin again.

The method combines bone marrow transplantation with islet cell transplantation. Results from a preclinical trial of the treatment led by Defu Zeng, M.D., associate professor in the departments of Diabetes and Metabolic Diseases Research and Hematology & Hematopoietic Cell Transplantation, were published online on June 8 in the journal Diabetes.

Clockwise from top, Jeremy Racine, Defu Zeng and Miao Wang (Photo by p.cunningham)

In type 1 diabetes, patients’ own immune cells mistakenly attack insulin-producing cells in the pancreas, decimating the cells and leaving patients without enough insulin to function. One investigational therapy for severe type 1 diabetes is islet cell transplantation: a procedure in which physicians transplant donated insulin-producing islet cells into the patient’s liver. These cells then supply insulin.

Today’s islet cell transplantation has challenges, however. Physicians must gather islet cells from the pancreases of two deceased donors to get enough cells for one transplant, and these donated organs are scarce. Patients’ immune cells may attack the transplanted cells, and immunosuppressive medications sometimes keep the new cells from working well. The liver, too, can be an inhospitable site for these transplanted cells.

“Islet cell transplants usually only provide two to three years of insulin independence for most recipients,” said co-lead author Miao Wang, M.D., Ph.D., postdoctoral fellow in Zeng’s lab. “We wanted to find a way to extend that insulin independence.”

The City of Hope team’s strategy aims to keep the immune system from attacking islet cells by resetting the body’s defenses through a bone marrow transplant, or BMT.

Experts today consider BMT too risky for conditions that are not immediately life-threatening, since it requires patients to undergo radiation or chemotherapy to kill their own bone marrow and immune cells before transplantation. But Zeng and his colleagues previously found a gentler way to prepare a patient with diabetes to receive a BMT.

“Our pretransplantation conditioning method uses no radiation and is much less toxic,” explained co-author Jeremy Racine, a Ph.D. candidate in Zeng’s lab. The method uses a special anti-CD3 antibody to battle harmful immune cells.

By pairing this gentler BMT with islet cell transplantation, the team members were able to reverse type 1 diabetes in mice by implanting only 10 percent of the number of islet cells used in a traditional islet cell transplant. They also successfully implanted the cells in the pancreas, rather than the liver, which may allow the cells to function and reproduce themselves better.

“By requiring fewer islet cells for transplantation, this strategy would reduce the number of donor organs needed, and would make the native pancreas a suitable site for islet grafts,” Zeng said. “The new regimen appears to be able to overcome all the major obstacles currently facing islet transplantation procedures.”

The researchers will continue preclinical testing to establish groundwork for potential human clinical trials. City of Hope study authors included Chunyan Zhang, Ph.D., a co-lead author and former Zeng lab member as well as Hongjun Liu, Chia-Lei Lin, Indu Nair, Joyce Lau and Ivan Todorov, Ph.D., associate research professor. Authors also included Yu-An Cao, Ph.D., of the Stanford University School of Medicine, and Mark Atkinson, Ph.D., of the University of Florida College of Medicine.

The National Institutes of Health and Juvenile Diabetes Research Foundation supported the research.