Immune System Discovery May Lead To Preventive Therapy For Diabetes

The investigators report in the Nov. 20 issue of the Proceedings of the National Academy of Sciences that they were able to protect diabetes-prone mice from developing the disease by activating immune system cells known as iNKT cells. When they dismantled the “go” signal for producing these cells, the animals’ diabetes worsened.

“As the mice progress in their disease, the number of these cells decreases,” says the study’s senior author, Brian Wilson, MD, PhD, of Dana-Farber. “Mice that are resistant to diabetes, by contrast, continue to accumulate the cells in their pancreatic tissue.

“Because iNKT cells work in much the same way in mice and humans, techniques for increasing the production of these cells could be the basis of preventive treatments for people with a genetic risk of diabetes.”

The job of iNKT cells is to regulate the immune system’s response to infections and other disorders, ensuring that only diseased tissue, not healthy tissue, is targeted for attack. Type I diabetes, an “autoimmune” disorder, occurs when the immune system mistakenly attacks healthy insulin-producing cells in the pancreas. The loss of insulin impairs the body’s ability to utilize sugar, leading to a host of health problems including kidney damage, nerve damage, and loss of vision.

Scientists have known that a loss of iNKT cells causes diabetes to worsen in non-obese diabetic (NOD) female mice, which have an inborn tendency to develop the disease. The falloff in the number of the cells apparently weakens the immune system’s ability to rein in an errant attack on the pancreas.

The new study involves a closer look at the body’s mechanism for activating iNKT cells. The mechanism involves a class of cells known as dendritic cells, whose role is to alert the rest of the immune system to the presence of infection or another health problem. The surface of dendritic cells is studded with proteins called CD1d, which display lipids, or fat, molecules. One such potent activating lipid is known as alpha-galactosylceramide. When iNKT cells sense the presence of these molecules, the cells are activated, reining in the immune system’s attack on normal tissue.

In the new study, Wilson and his colleagues administered alpha-galactosylceramide to NOD female mice to see if it would prevent them from developing diabetes. “It did, potently,” says Wilson, who is also on staff at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School. In the second part of the study, investigators silenced the gene for CD1d, preventing dendritic cells from displaying alpha-galactosylceramide on their surface. The result was that iNKT cells were not activated and the mice, which had a pre-diabetic condition, went on to develop full-blown diabetes.

In mice and people with pre-diabetic conditions, the normal interactions between dendritic cells and iNKT cells do not occur properly, leaving them more likely to get diabetes. The findings of the Dana-Farber study suggest that such individuals could be helped by increasing their supply of iNKT cells, perhaps by administering alpha-galactosylceramide to them.

“The success of our work in mice lays the groundwork for a clinical trial of this therapy in people at high risk for diabetes,” Wilson says. “Preventing pre-diabetic conditions from progressing would be an important benefit to about one in 500 people in the U.S.”

###The paper’s other authors are Yuri Naumov, Rudolph Gausling and Jack Strominger, Dana-Farber; Keith Bahjat and Michael Clare-Salzer, College of Medicine, University of Florida, Gainesville; Roshini Abraham, Mayo Clinic, Rochester, Minn.; Mark Exley and Steven Balk, Beth Israel Deaconess Medical Center, Boston; and Yasuhiko Koezuka, Kirin Brewery, Gunma, Japan.

The study was supported by the National Institutes of Health and the Juvenile Diabetes Research Foundation International.

Dana-Farber Cancer Institute (http://www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), a designated comprehensive cancer center by the National Cancer Institute.