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Research discovery identifies new strategy against diabetes


UCSF scientists have identified a protein on T cells of the immune system that triggers type 1 diabetes in mice when it interacts with another protein in the pancreas. They have shown that blocking the interaction prevents development of diabetes without weakening normal immune defenses or causing measurable side effects. The success provides a promising strategy against human type 1 diabetes, since the T cell protein has a counterpart in the human immune system, the scientists say.

The research is being published online June 15 by the journal Immunity.

The T cell protein, known as NKG2D, is a receptor on the surface of CD8+ T lymphocytes. The second protein, called RAE-1, has been found on cells infected by bacteria or viruses where it binds to NKG2D, alerting CD8+ T cells and other immune system molecules to attack and eliminate the pathogen.

T cells normally attack and destroy invading pathogens, but in type 1 diabetes, they mistakenly destroy the body’s insulin-producing islet cells.

"We knew that RAE-1 and its immune receptor were involved in anti-pathogen reactions," said Lewis Lanier, PhD, UCSF professor of microbiology and immunology and one of the paper’s senior authors. "The surprising finding is that RAE-1 is present in the pancreas of mice with autoimmune diabetes and if we prevent RAE-1 from binding its receptor on immune cells it can have a profound effect on autoimmunity. And treatment causes no observable side effects."

The researchers showed that treating the mice with an antibody that blocks the interaction of RAE-1 with the NKG2D receptor is completely effective against development of type 1 diabetes, Lanier said.

"You don’t need a calculator to tell the treatment group from the placebo group. It’s 100 percent effective," he said.

In addition to this newly discovered pathway, UCSF scientists have developed other strategies to block autoimmune disease by selectively interfering with receptors present on the surface of T cells. Jeffrey Bluestone, PhD, director of the UCSF Diabetes Center and a senior author with Lanier on the new paper, developed genetically engineered antibodies against CD3, another key T cell receptor that is required to trigger an autoimmune attack. The strategy has helped arrest early stages of human type 1 diabetes and rejection of islet cell transplantations in clinical trials. The treatment produces only minor side effects.

"The aim of selectively blocking molecules of the immune system is to prevent autoimmune disease without destroying all immune defenses -- and with a minimum of side effects, " Bluestone said. "Blocking the NKG2D receptor is even more selective than the anti-CD3 approach. What’s exciting about this finding is that if antibodies against this pathway can be developed into a treatment for human autoimmune disease, it would represent a very specific therapy targeting only a very small population of immune cells most involved in the disease."

The scientists studied diabetes development in "non-obese diabetic" (NOD) mice, considered the gold standard for type 1 diabetes research because disease progression in the mice mirrors the process in humans. In these mice, CD8+ T cells invade the pancreas when the mice are three weeks old, and diabetes develops 10 to 20 weeks later.

The team found that T cells invading the pancreas of the diabetic NOD mice expressed NKG2D and that insulin-producing islet cells in the pancreas produced the RAE-1 protein, promoting T cells to attack the islet cells. Normal, healthy mice did not produce RAE-1 in the pancreas. Treatment with the antibody that blocks RAE-1 from its receptor prevented development of diabetes in the NOD mice, the researchers reported.

The UCSF scientists expect that development of a "humanized" antibody to human NKG2D may provide an effective type 1 diabetes treatment. Other research has recently shown that the NKG2D on T cells may be involved in rheumatoid arthritis, so blocking NKG2D signaling may prove a useful strategy against a number of autoimmune diseases, the scientists conclude.

Lead author on the study is Kouetsu Ogasawara, PhD, a post-doctoral scientist in Lanier’s lab. Co-authors are Jessica A. Hamerman, PhD, and Lauren R. Ehrlich, PhD, postdoctoral fellows in Lanier’s lab; Helene Bour-Jordan, PhD, in the UCSF Diabetes Center; and Pere Santamaria, MD, PhD, professor of microbiology and infectious diseases at the Julia McFarlane Diabetes Research Centre, University of Calgary.

Support for the research was provided the National Institutes of Health, the Juvenile Diabetes Research Foundation and others.

Wallace Ravven | EurekAlert!
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