Photo:Nancy Kerkvliet, OSU immunotoxicologist, researches chemicals that suppress the immune system. Photo by Stephen Ward
Oregon State University researchers have discovered a chemical that blocks Type 1 diabetes in laboratory mice and may work the same way in humans.
The chemical, nicknamed BBQ, works at the genetic level to prevent a rogue immune response from destroying insulin-producing cells in diabetic mice, researchers said.
If it works the same way in humans, it could yield a breakthrough therapy for Type 1 diabetes and possibly have applications in other autoimmune diseases as well, including colitis, psoriasis and multiple sclerosis.
“This compound has a very targeted effect, and it’s safe at therapeutic doses in mice,” said Nancy Kerkvliet, a professor in OSU’s College of Agricultural Sciences and lead researcher on a new study just published in the Journal of Immunology.
“If it works in human clinical studies, we envision a therapy that could be started early to block the onset of Type 1 diabetes, and maybe even cure it in the long run,” she said.
Type 1 diabetes — sometimes called juvenile diabetes — causes the immune system to destroy insulin-producing cells in the pancreas. The disease often doesn’t show symptoms until the pancreas damage is irreparable, Kerkvliet said.
The body needs insulin to move food energy, in the form of glucose, from the bloodstream into tissues. Type 1 diabetics usually have to take artificial insulin for the rest of their lives. Among U.S. children up to age 19, the incidence of Type 1 diabetes has increased 21 percent from 2001-2009, according to a 2014 study in the Journal of the American Medical Association.
In the new research, Kerkvliet’s laboratory worked with mice bred to develop Type 1 diabetes, one group of which received BBQ three times a week. A control group of untreated mice developed diabetes, while the BBQ-treated mice were protected from disease.
The treated mice showed virtually no inflammation in their pancreatic “islets” — the pockets of cells in the pancreas that make insulin, Kerkvliet said. Inflammation of these islets is a telltale sign of the disease. In contrast, all of the control mice showed extensive islet inflammation.
Researchers say that BBQ works by binding to a protein within cells called the aryl hydrocarbon receptor, or AhR, which then regulates genes that influence immune responses.
After the BBQ locks onto the AhR, it moves into the nucleus of T cells — white blood cells that coordinate the body’s immune response. There, AhR latches onto the DNA and changes the messaging of the genes, which prevents the T cell from attacking the pancreatic islets.
Allison Ehrlich, a postdoctoral fellow in the Kerkvliet Laboratory and co-researcher on the study, said the beauty of BBQ is that it works without shutting down the rest of the immune system, unlike current steroid-based immunosuppressants.
Erlich said that T cells are born “naïve,” and “learn” to attack harmful pathogens. As this happens, the cells become more specialized — a process called differentiation.
“When BBQ binds to the AhR, it stops new T cells from differentiation,” Ehrlich said. “The ‘memory’ T cells, those that already exist, aren’t affected. So the body stays protected against pathogens it has been exposed to in the past.”
In earlier studies, Kerkvliet discovered that the chemical TCDD — better known as dioxin — also binds to AhR and prevents Type 1 diabetes in mice. But dioxin is not a good candidate for an immune-suppression therapy, she said, because it lingers in the body for years after exposure and is considered a toxic chemical.
“So we went looking for another compound that would function in the same way but without the bad effects,” said co-researcher Siva Kolluri. After screening tens of thousands of chemicals, Kolluri’s laboratory hit upon BBQ. Unlike dioxin, BBQ has a good safety profile, he said.
Kerkvliet said BBQ also has potential for treating other autoimmune diseases such as colitis, psoriasis and multiple sclerosis. It holds promise for alleviating graft-versus-host disease by suppressing the immune response in, for example, organ-transplant surgery.
The study was funded by the National Institute of Environmental Health Sciences, National Institutes of Health and appears in the January 2016 issue of The Journal of Immunology.
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