by Kathleen O’Neil

City of Hope researchers are investigating a way to treat type 1 diabetes that could reverse the disease and allow patients to begin making their own insulin again.

Their method would use bone marrow transplantation to replace patients’ malfunctioning immune cells. In type 1 diabetes, patients’ immune cells attack their own insulin-producing cells, leaving them without enough insulin to function.

Results from a preclinical trial of the treatment led by Defu Zeng, Ph.D., assistant professor in the divisions of Diabetes, Endocrinology & Metabolism and Hematology & Hematopoietic Cell Transplantation, appeared in the Feb. 13 issue of the Proceedings of the National Academy of Sciences.

Experts today consider bone marrow transplantation, or 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. Zeng and his colleagues found a gentler way to prepare a patient with diabetes to receive a BMT using donated cells.

“This approach is exciting because it has the potential to cure diabetes,” Zeng said. “Since our pretransplantation conditioning method is much less toxic, it could allow bone marrow transplantation to be used to treat a variety of autoimmune diseases for which total-body radiation or chemotherapy is too damaging to justify the benefits.”

Zeng and colleagues conduct the research in the Leslie and Susan Gonda (Goldschmied) Diabetes and Genetic Research Center, a City of Hope building whose opening in 1997 significantly expanded basic and clinical diabetes research at the Duarte, Calif., campus.

Of the more than 20.8 million people with diabetes in the United States, 5 to 10 percent have type 1. Although it can develop at any age, type 1 diabetes most commonly appears in children and young adults. One in every 400 to 600 children has the disease.

Currently incurable, the disease must be controlled with insulin injections.

Healthy people produce immune cells, called T-cells, which attack foreign material. But in those with type 1 diabetes, T-cells mistakenly attack beta cells, the cells that produce insulin in the pancreas.

Through a BMT, though, physicians may introduce healthy, functioning immune cells from a donor, allowing insulin-producing cells to slowly grow back and produce insulin again.

The team’s BMT method eliminates the need for damaging chemotherapy or radiation by using an antibody to inactivate the host’s immune T-cells instead. That allows donated T-cells to kill the host’s T-cells — so the donated immune cells can take over the body’s defensive duties. Zeng found that without any pretreatment, the host’s T-cells kill the donated T-cells within 24 hours. Researchers previously used the same antibody, anti-CD3, in clinical trials to prevent rejection of transplanted organs.

Zeng’s method was successful in preclinical trials in mice: None of the mice receiving BMT and anti-CD3 developed diabetes again, compared to 89 percent of the control group. Examination of their pancreases showed that their insulin-secreting cells were also free from attack by T-cells, while the opposite was found in untreated mice.

The researchers will continue preclinical testing to establish groundwork for potential human clinical trials.

Zeng conducted the research with postdoctoral researcher Chunyan Zhang, Ph.D., research associate Vivian Lin, Ivan Todorov, Ph.D., associate research scientist in the Department of Diabetes, Endocrinology & Metabolism, Stephen Forman, M.D., Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation, and Fouad R. Kandeel, M.D., Ph.D., director of the Department of Diabetes, Endocrinology & Metabolism.

The National Institutes of Health (NIH) and the Juvenile Diabetes Research Foundation (JDRF) support the work. Support from the Gonda Foundation has been pivotal in diabetes research and in developing City of Hope’s islet cell transplant program, which has been designated by the NIH and JDRF as one of seven islet cell resource centers in the nation.