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OSU hunts for dioxin substitutes to fight autoimmune diseases
January 15, 2010
Nancy Kerkvliet, an immunotoxicologist at Oregon State University, and research assistant Sam Bradford use a flow cytometer to analyze cells in their search for chemicals that suppress the immune system. Photo by Lynn Ketchum.
CORVALLIS, Ore. – Scientists at Oregon State University are hunting for substitute chemicals for a toxic dioxin to fight diseases that are triggered by haywire immune systems attacking the body.
The dioxin, known as TCDD, has been shown to suppress the immune system in animals and prevent type 1 diabetes in mice. OSU researchers hypothesize that it could do the same in people. But they aren't considering it as a treatment because it has produced bad side effects in animals and can cause chloracne, a disfiguring skin disease in humans.
Instead, they're looking for safer alternatives that would function like TCDD, which is perhaps best-known for its presence in the jungle-decimating Agent Orange herbicide used during the Vietnam War.
If successful, the chemicals might be able to prevent and treat autoimmune diseases like rheumatoid arthritis, multiple sclerosis, psoriasis and type 1 diabetes.
"Immunosuppressive drugs are already used to treat these diseases, but they can create their own problems," said Nancy Kerkvliet, an OSU immunotoxicologist who is helping conduct the research. "Consequently, the new way of thinking is to use a mixture of drugs at lower doses to reduce the side effects caused by higher dosages of individual drugs. Through our research, we're hoping to discover new drugs that will expand the choices of drugs that can be used."
To help with that effort, the American Recovery and Reinvestment Act of 2009 provided Kerkvliet and her team with $1.8 million.
Kerkvliet has been studying dioxins for three decades. She published a paper last year in the journal Immunotherapy that showed that in mice TCDD can prevent type 1 diabetes, which occurs when the immune system attacks the pancreas and kills the cells that produce insulin. The mice used in the study develop type 1 diabetes spontaneously because of genetic defects in their immune system. However, of the 12 mice that were treated with TCDD, none developed the disease. Eight of the 11 mice that weren't treated with it developed diabetes by 28 weeks of age.
Kerkvliet said that TCDD's effect on the immune system of mice works like this: First, it binds to a protein called the aryl hydrocarbon receptor (AhR) found inside a cell. The united TCDD and AhR then pass into the nucleus, latch onto DNA and turn certain genes on or off. Kerkvliet's research suggests that this process produces regulatory T cells, which then shut down the immune system's response. This then suppresses the development of diabetes, she said.
To help her find alternatives for TCDD, cancer biologist Siva Kolluri and his crew are screening 50,000 chemical compounds in search of ones that will bind to AhR and induce regulatory T cells. So far, they've tested about 5,000 in cell-based assays for their ability to activate AhR, Kolluri said.
"There have been some promising hits," he said. "We need to make sure that they work only through this receptor. We also have to make sure they're not toxic. We don't want them to have any of the bad effects that TCDD has."
Later, Kerkvliet and her team will test the compounds in mice to see if they prevent type 1 diabetes. If they do, Kerkvliet believes that it would be likely that they would also fight other autoimmune diseases because most of these diseases are also controlled by regulatory T cells. Of course, any chemicals that are successful in treating laboratory animals would eventually have to be studied in humans to see if the effects are the same.
Source: Nancy Kerkvliet, Siva Kolluri