Mouse study suggests diabetes prevention.

Mouse study suggests diabetes prevention

Boston researchers have identified two types of immune-system cells with opposing effects that determine whether or not diabetes-prone mice will develop the disease. By injecting the mice with a toxin that targets the cell type that destroys the body's insulin factories, they have tipped the balance in favor of the insulin-protective cell type, halting diabetes onset.

The work points to a possible preventive treatment for people at high risk of insulin-dependent (Type I) diabetes and adds to the evidence linking the disease with a misdirected immune-system attack, the researchers say.

Vicki E. Kelley of Harvard Medical School and her colleagues began their study after reports that certain T-cells--a class of immune-system cell--invade the insulin-producing islet cells in the pancreas of prediabetic mice. The invasion causes insulitis, or inflammation of the islets, which appears to be a necessary first step for the development of diabetes in both mice and humans. But Kelley noted that some prediabetic mice remained healthy despite insulitis. With Terry Strom of Harvard and John R. Murphy of Boston University, she theorized that a molecular tug-of-war with another group of T-cells -- acting as islet-cell preservers--might explain the phenomenon.

The researchers removed and cultured the T-cells involved in the earliest stages of islet invasion, reasoning that those cells might have the most potency for triggering or preventing diabetes. They isolated and cloned a subgroup of these cells featuring some unusual properties: They belonged to a class known as CD4, and they triggered diabetes when injected into other prediabetic mice. The investigators also cloned another type of T-cell -- members of a class called CD8, many of which suppress immune function. When they injected prediabetic mice with CD8 cells and with spleen cells known to accelerate diabetes onset, the mice did not develop the disease. In contrast, prediabetic mice injected only with the spleen cells developed diabetes within three weeks.

"Our work demonstrates that a delicate balance between autoaggressive T-cells and those which suppress immune reactions determines whether autoimmunity is limited or progresses to diabetes," Kelley reported this week at a National Kidney Foundation science writers' briefing in New York City. Diabetes accounts for about 25 percent of all kidney failure.

Strom and Murphy established that the insulitis-associated CD4 cells produce a chemical called interleukin-2 and also have surface receptors for it. Knowing that interleukin-2 stimulates these cells to multiply -- and presumably to attack islet cells -- they used some genetic sleight-of-hand to thwart the invasion process. They created a hybrid of diphtheria toxin and interleukin-2 that binds exclusively to CD4 cells possessing the receptor and kills them.

Kelley, Strom and Murphy found the toxin prevented prediabetic mice from developing the disease, even though they had first injected these mice with aggressive islet-destroying immune cells taken from mice with full-fledged diabetes. Kelley says the treated mice retained functioning immune systems after toxin therapy ended--an important consideration for human therapy.

She notes that researchers at M.D. Anderson Hospital in Houston have begun a clinical trial of the hybrid diphtheria toxin's potential for destroying adult leukemia and lymphoma cells possessing interleukin-2 receptors. Trials in diabetes-prone humans may begin later this year, she adds. Such studies have become feasible in recent years with the discovery that certain indicators in blood can help identify people at risk of diabetes (SN: 7/18/88, p.389).

"We are now at the stage where we can identify people at risk," says immunologist George S. Eisenbarth of the Joslin Diabetes Center in Boston. "The question is whether the interleukin-2 toxin is the most effective treatment."