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January 11, 2007

Pitt researchers prevent diabetes in mice

Pitt researchers have prevented type 1 diabetes in mice, research that may have significant implications for the prevention of the disease in humans.

Type 1 diabetes (also known as juvenile diabetes) is an autoimmune disorder in which the body attacks insulin-producing cells in the pancreas, causing elevated blood sugar levels that can damage organs or even lead to death. Some 700,000 Americans are affected by the disease.

Results of the research, which used an antibody against a receptor on the surface of immune T-cells to prevent diabetes in the mice, were published in the January issue of the journal Diabetes. Senior author William M. Ridgway, assistant professor in the School of Medicine’s Department of Rheumatology and Clinical Immunology, said this therapy, if given early enough, may offer a way to prevent the onset of type 1 diabetes in genetically at-risk people.

Ridgway estimated it could take two years of research to determine whether human T-cells also express the receptor and if the T-cells of diabetics differ from those of non-diabetics. Other researchers currently are working on those questions and Ridgway estimated that it might be a decade before researchers unravel the genetics behind diabetic susceptibility.

“The genetics of human diabetes is a huge jigsaw puzzle. If this piece of the puzzle is playing a role in humans (which we can find out in the next couple years), then the next question before it could be applied is how it fits into the rest of the puzzle. You would have to identify many pieces of the puzzle in order to achieve the goal of being able to predict which people, with which genetic makeup, will get diabetes,” he said.

The issue is complicated, Ridgway said, with genetics playing a large role, but with environment also affecting who might become diabetic.

In the recent research, Ridgway’s team treated non-obese diabetic (NOD) mice with an antibody (a protein produced by the immune system that recognizes and helps fight infections and other foreign substances in the body) directed against a receptor known as CD137 on the surface of T-cells. Treating NOD mice with the anti-CD137 antibodies significantly suppressed the development of diabetes, while most of the control mice developed diabetes by the time they were six months old.

The antibody therapy did not appear to cure the NOD mice because the researchers still could see lymphocytes in their pancreatic islets, an indicator of pancreatic inflammation and autoimmunity.

When the researchers isolated cells from the spleens of the antibody-treated mice and injected these cells into immune-deficient NOD mice, seven of the nine recipient mice developed type 1 diabetes, indicating that the donor mice still harbored pathogenic T-cells.

On the other hand, when the researchers transferred a certain subset of T-cells from anti-CD137-treated mice that expressed two other receptors known as CD4 and CD25 to other immune-deficient NOD mice, it prevented the onset of diabetes in the recipient mice.

“Our studies and others suggest that CD137 plays a significant role in the development of and genetic predisposition to type 1 diabetes. In this study, for the first time, we have demonstrated that CD137 antibody therapy can suppress the development of type 1 diabetes in mice and that the effect is dependent on the induction of a certain subset of regulatory T-cells.”

In mice, Ridgway said, the next step is to isolate and characterize the T regulatory cells that specifically express this CD137 molecule.

“If we can demonstrate this same genetic predisposition and therapeutic effect in human type 1 diabetes patients, then this may prove to be a significant step toward preventing this disease before it can take hold,” Ridgway said.

This research was funded by the National Institutes of Health through the Autoimmunity Centers of Excellence mechanism.

Other Pitt researchers involved in the study were Junichiro Irie, Yuehong Wu and Kritika Kachapati, of the Department of Rheumatology and Clinical Immunology.

—Kimberly K. Barlow

Filed under: Feature,Volume 39 Issue 9

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