IL-4 from Certain T Cells May Help Prevent Diabetes

NIAID grantees in Boston have discovered a link between a specific subset of immune cells in the blood and the development of type 1 diabetes. As they report in the January 8 issue of Nature, people predisposed to diabetes are more likely to develop the disease if these cells have lost the ability to produce a chemical messenger called interleukin-4 (IL-4).

The work was carried out in the laboratories of David A. Hafler, M.D., director of Molecular Immunology at the Center for Neurologic Diseases at Brigham and Women’s Hospital in Boston, and Jack L. Strominger, M.D., Higgins Professor of Biochemistry at Harvard University.

Dr. Hafler says, "Our results demonstrate a relationship between elevated IL-4 levels and resistance to the progression of diabetes. This relationship may represent a basic finding in the cause of type 1 diabetes."

Elaine Collier, M.D., chief of the Autoimmunity Section at NIAID, adds, "By offering insight into why certain persons are resistant to type 1 diabetes, these findings may eventually lead to new ways to prevent the disease."

Type 1 or insulin-dependent diabetes mellitus, which affects up to an estimated 800,000 people in the United States, usually develops before age 16. Although relatives of patients with the disease are at greater-than-average risk for developing the disease, most new patients do not have an affected relative.

The disease can be controlled with multiple daily injections of insulin, but most patients eventually develop one or more long-term complication such as blindness, kidney failure, heart attack, or nerve damage.

Type 1 diabetes is an autoimmune disease, meaning that the body’s immune cells, which normally fight off infections and cancers, attack healthy tissue instead. In this case, immune T cells attack the pancreatic islet cells that make insulin. The new finding suggests that the IL-4 produced by a specific subset of T cells may regulate the autoimmune reaction responsible for destroying the pancreatic islet cells.

An identical twin or triplet of a patient with type 1 diabetes is known to be at increased genetic risk for developing the same illness. What the Boston team set out to determine is why the condition develops in only some of those siblings.

"Our results demonstrate a
relationship between elevated
IL-4 levels and resistance to
the progression of diabetes."
Dr. David Hafler, Brigham
and Women's Hospital

When the researchers examined the number and function of a specific subset of T cells in five sets of identical twins and triplets, those relatives at high risk for diabetes but who had not developed the condition (non-progressors) were found to have cells that secreted two cytokines, interferon-gamma (IFN-g) and IL-4. The diabetic siblings’ cells secreted only IFN-g. Notably, half of these non-progressors had elevated serum levels of IL-4.

The researchers say their findings suggest that the higher levels of IL-4 produced by these cells in the non-diabetic siblings may be protecting them from developing the disease.

"If we can mimic what nature has done to produce IL-4, we may eventually develop new therapies for diabetes and other autoimmune diseases," says Dr. Strominger. "More research must be done before we reach that goal."

The study received primary funding from NIAID. The National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute, and the NIH Office of Research on Women’s Health also supported the research.

—by Laurie K. Doepel

Reference: SB Wilson et al. Nature 391:177-81 (1998).