Diabetes Forecast

When Good T-Cells Go Bad

In a way, type 1 diabetes is a case of mistaken identity, one that plays out in a vicious battle at the cellular level. The battle's victim is the pancreas, the organ responsible for producing the insulin the body needs to regulate the amount of glucose in the blood.

Every once in a while, the systems that protect us from infection and disease go wrong. When that happens, they can mistake the insulin-producing cells in the pancreas for something else entirely and attack—ravaging those cells and preventing them from producing the insulin the body needs. The result is type 1 diabetes.

With a grant from the American Diabetes Association, William Kwok, PhD, an immunologist based at the Benaroya Research Institute at Seattle's Virginia Mason Hospital and Medical Center, is leading a lab full of researchers in a search for the causes of this potentially deadly mix-up.

William Kwok, PhD
Principal Investigator, Benaroya Research Institute, Seattle
Research Funding
ADA Research Award funded in part by Mr. and Mrs. Thomas Dille, Fort Collins, Colo.

The keys, Kwok says, are T-cells, our immune system's front-line forces. The human body is stocked with a range of T-cells that act as a defense against potentially infectious invaders. "T-cells are very specific," Kwok says. "If you have a flu infection, some of the T-cells react against the flu." Others target entirely different infections or invaders—from cat dander to herpes.

As long as they are working properly, T-cells are a vital part of the body's resistance to illness. It's when they go wrong that the problems start. "T-cells as far as we understand it are one of the major first steps to set up an immune attack against insulin-producing cells," Kwok says. When that happens, some T-cells mistake cells in the pancreas for harmful invaders, turning against them and destroying their ability to produce insulin.

Kwok and his team are trying to find out why some T-cells go bad. To understand what's going on at the cellular level, they use a recently developed substance called a tetramer, a synthetic protein that mimics the texture and appearance of cellular structures.

First developed about a decade ago, these reagents can be used to identify T-cells that recognize different targets, including those that attack the insulin-producing cells in the pancreas. "It's like a fish taking the bait," says Eddie James, a researcher in Kwok's lab.

The tetramers allow scientists to study T-cells' behavior in a laboratory setting. The technique has been used to look at the role of T-cells in a variety of immune system diseases and illnesses, from simple springtime allergies to genetic conditions like multiple sclerosis. Kwok and his team have themselves used tetramers to study everything from herpes and hepatitis to anthrax. But untangling the causes of type 1 diabetes "is among the tougher cases," James says. "It's a complex disease, genetically and environmentally."

Kwok, James, and their colleague Xinhui Ge lure the T-cells that cause type 1 diabetes onto special tetramer-coated chips. These specially prepared pieces of glass are about the length and width of a finger and painted with tetramers in different mixtures, designed to "hook" different types of T-cells.

The tetramer-coated chips are incubated with T-cells from blood samples taken from type 1 diabetes patients. The aggressive, problematic T-cells latch on to the tetramer-coated chips, forming little clusters of cells that can then be analyzed.

The process is still in its earliest stages. Kwok and his team currently need about two weeks to perform a single "assay," or T-cell test. "The ideal situation, if things develop really well, is we could do it in a couple of hours," Kwok says. The team's ultimate goal is to develop a laboratory test that can tell which T-cells are likely to go after the insulin-producing beta cells in the pancreas. That way, doctors would know in advance which patients have malfunctioning T-cells long before they begin attacking the pancreas.

The head start would be critical. "By the time diabetes is diagnosed, most of the damage has already been done," says James. "It would be ideal to diagnose beforehand." And, ultimately, scouting out the cellular battlefield could yield other insights on how to fight type 1 diabetes.

To sponsor an ADA research project at the Research Foundation's Pinnacle Society level of $50,000 or more, call Elly Brtva, MPH, managing director of Individual Giving, at (703) 253-4377, or e-mail her at ebrtva@diabetes.org.

Andrew Curry is a freelance writer.



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