Diabetes Treatment Fits to a T Cell

Diabetes is the seventh-leading cause of death in the U.S. and is a major contributor to heart disease, blindness, and even leg and foot amputations. Long before the chronic disease attacks various parts of the body, however, the body attacks itself to cause diabetes. Dr. Paul Hess, an assistant professor in the College of Veterinary Medicine, wants to stage his own attack and destroy the cells believed to be responsible for Type 1 diabetes, which afflicts as many as 3 million children in the U.S.

Type 1 diabetes develops when T cells, white blood cells that normally protect the body from various illnesses, get a signal to destroy cells in the insulin-producing areas of the pancreas called islets. Researchers aren’t sure why the signal is issued, but Hess says there are a couple dozen genetic factors that place some children at higher risk. “About 90 percent of the T cells your body makes are either killed or turned off because they are capable of attacking healthy tissue,” he says. “In some people, these T cells aren’t eliminated or restrained, and they then ignore all of the body’s signals that say, ‘Don’t do this.’”

Type 1 diabetes develops when T cells get a signal to destroy cells in the insulin-producing areas of the pancreas.

Most of Hess’ research has been in oncology, but he says diabetes treatments offer him a look at “the opposite side of the coin” from cancer. Tumors are usually ignored by the body’s immune system, he says, while an autoimmune disorder involving T cells causes Type 1 diabetes. “To develop a cancer vaccine, you need to overcome the body’s tolerance of tumor cells,” he says. “Conversely, you need to promote tolerance of healthy tissue to defeat diabetes.”

A synthetic molecule known as a tetramer can deliver a toxin that knocks out the rogue
T cells.

The best way to do that is to target the rogue T cells. With funding from the Juvenile Diabetes Research Foundation, Hess used a synthetic molecule known as a tetramer to deliver a toxin that knocks them out. The four proteins that form the outer surface of the tetramer can be directed to bind to specific T cells. Saporin, a protein that shuts down cellular activity, is then inserted into the cell’s middle. Tests in mice have shown that diabetes-causing T cells that are targeted by the tetramer take in the saporin and are killed, delaying the onset of the disease.

Hess is working with an immunologist from UNC-Chapel Hill on a National Institutes of Health grant to identify the specific type of T cell that attacks the pancreas. “There is a mixture of T cells in the islets, and there’s good evidence that one type gets the process started and then enlists the others to join in the attack,” he says. “We need to find the real culprit to protect children from this debilitating disease.”

 

Dr. Paul Hess uses synthetic molecules to kill off the rogue T cells that cause juvenile diabetes. The four-legged tetramers, shown in the upper left of the first two illustrations below, are designed to bind to the T cells. As the cell ingests and breaks down the tetramer, it releases a toxin that kills the cell.