City of Hope researchers have found that bone marrow transplantation with islet cell transplantation shows promise as a treatment for late-stage type 1 diabetes. This combination may enable patients to make their own insulin again. Results from laboratory research led by Defu Zeng, MD, associate professor in the departments of Diabetes Research and Hematology & Hematopoietic Cell Transplantation at City of Hope, were published online this month in the journal Diabetes.
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. More than 23.6 million people in the United States have been diagnosed with diabetes, and an estimated 5 to 10 percent of these individuals have type 1 diabetes, according to the American Diabetes Association.
One investigational therapy for severe type 1 diabetes is islet cell transplantation, a procedure in which physicians transplant donated islet cells into the patient’s liver, where they can engraft, take root and produce insulin.
Yet, there are several challenges to long-term islet transplantation success. Patients’ immune cells may again attack the transplanted cells, and immunosuppressive medications sometimes keep the new cells from properly functioning. The liver also 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, MD, Ph.D., postdoctoral fellow in Zeng’s lab. “We wanted to find a way to extend that insulin independence.”
The research team’s strategy aims to keep the immune system from attacking islet cells by resetting the body’s defenses through a bone marrow transplant (BMT).
Many experts 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. However, Zeng and his colleagues previously found a gentler way to prepare a patient with diabetes to receive a BMT that did not require high levels of chemotherapy and radiation.
“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.
“Our new anti-CD3 based conditioning regimen for BMT may have a chance to improve the effectiveness of islet transplantation therapy, because our studies demonstrated that under a radiation-free, nontoxic, anti-CD3-based conditioning regimen, bone marrow transplantation not only provides immune tolerance to islet transplants, but also markedly reduces the required amount of donor islets for reversal of late-stage refractory type 1 diabetes,” added Zeng.
By pairing this anti-CD3 regimen for BMT with islet cell transplantation in the laboratory, the team members reversed type 1 diabetes while implanting only 10 percent of the number of islet cells used in a traditional islet cell transplant. In the laboratory, they also successfully implanted the cells in the pancreas, rather than the liver, which may allow the cells to function and better reproduce themselves.
“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 their laboratory research to establish the groundwork for potential human clinical trials. City of Hope study authors included Chunyan Zhang, 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 scientist in the Department of Diabetes Research. 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.
About City of Hope
City of Hope is a leading research and treatment center for cancer, diabetes and other life-threatening diseases. Designated as a Comprehensive Cancer Center, the highest honor bestowed by the National Cancer Institute, and a founding member of the National Comprehensive Cancer Network, City of Hope’s research and treatment protocols advance care throughout the nation. City of Hope is located in Duarte, Calif., just northeast of Los Angeles, and is ranked as one of “America’s Best Hospitals” in cancer and urology by U.S.News & World Report. Founded in 1913, City of Hope is a pioneer in the fields of bone marrow transplantation and genetics. For more information, visit www.cityofhope.org.
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City of Hope press release