How suppressing the immune system may prevent type 1 diabetes

A new study at Yale School of Medicine has uncovered the mechanism by which a targeted suppression of the immune system may prevent type 1 diabetes or induce sustained remission. The study appears in Science Translational Medicine.

Type 1 diabetes is an autoimmune disease -- the immune system goes into overdrive and attacks the body’s normal cells instead of foreign invaders. In type 1 diabetes, the immune system targets and eventually destroys the insulin-producing beta cells of the pancreas, leading to increased levels of blood sugars.

Researchers have undertaken clinical trials to study whether suppressing the inflammatory response of the immune system can prevent such misguided attacks. The monoclonal antibody teplizumab (anti-CD3) is currently being tested in clinical trials for prevention of type 1 diabetes and treatment of new-onset diabetes. Although early data has been encouraging, the mechanism by which teplizumab might work has not been understood, until now.

Working with a mouse model with a functional human immune system, the Yale team focused on the effect of teplizumab on CD3-positive immune cells, which are key to the development of type 1 diabetes

The researchers found that teplizumab induced the immune system’s T cells to migrate from the circulatory and lymph systems to the small intestine, where they produced the anti-inflammatory protein interleukin-10. "When these cells returned to circulation, they had become regulators of the immune response," said study author Kevan Herold, M.D., professor of immunobiology at Yale School of Medicine and principal investigator of Yale’s clinical trials in the prevention of type 1 diabetes.

Co-author Richard A. Flavell, professor of immunobiology and a Howard Hughes Medical Institute investigator, led a study published last summer that defined the mechanism by which anti-CD3 drugs work in mice. "In this new study, we address the way this investigational drug works on human cells in a mouse model," Flavell said. "The results are exciting and predictive of how this compound would work in people."

The Yale research opens the way for further clinical trials that may explore the extent to which such targeted immunosuppression in humans may prevent the onset of type 1 diabetes or restore insulin-producing capability in early-onset patients. "This study demonstrates how translational medicine can work for the benefit of patients," added author Frank Waldron-Lynch, M.D., clinical fellow in endocrinology.

Other authors are Octavian Henegariu, Songyan Deng, Paula Preston-Hurlburt and James Tooley of Yale School of Medicine.

Yale School of Medicine is one of the leading clinical trial sites for the nationwide consortium investigating prevention of type 1 diabetes, and one of just six infusion sites.