The long road toward a treatment for autoimmune diseases
Nancy Kerkvliet began her career as an immuno-toxicologist in the 1970s, at the end of the Vietnam War and the beginning of the environmental movement. At the time, concern was mounting about the health effects of Agent Orange, an herbicide used by the US military to defoliate Vietnamese jungles.
Kerkvliet has focused much of her 40 years of research on how environmental contaminants affect human health, including TCDD, a particularly toxic dioxin compound formed as an unwanted byproduct in the production of Agent Orange. Dioxins are linked to many adverse human health effects, depending on level of exposure, including suppression of immune function.
Kerkvliet discovered that the ability of TCDD to suppress the immune system in mice was linked to the activation of a protein called the Ah receptor. Because humans also have Ah receptors, she began to question if the properties of dioxin could be directed toward fighting diseases caused by inappropriate immune responses.
“Millions of people throughout the world suffer from diseases associated with an overactive and misdirected immune response,” Kerkvliet said. “These disorders, known as autoimmune diseases, include multiple sclerosis, Crohn’s disease, and Type 1 diabetes.” She saw a link between the underlying immune defects and the properties of dioxin that could counteract those defects.
Kerkvliet explored this possibility using a mouse model of Type 1 diabetes. In both mice and humans, Type 1 diabetes develops when the immune system attacks healthy insulin-producing cells in the pancreas. Insulin is required for cells to use glucose; Type 1 diabetes patients are completely dependent on synthetic insulin.
“The idea of using dioxin as a treatment for Type 1 diabetes was initially unimaginable,” Kerkvliet said. “However, it worked!” The treatment successfully prevented the development of Type 1 diabetes in all of the treated mice. Kerkvliet’s work demonstrated that the immune-suppressing ability of dioxin could be used effectively to limit damage to the pancreas, thus allowing the mice to produce enough insulin on their own to maintain normal blood sugar levels.
However, the trouble remained that dioxins persist in the body for a very long time and excessive exposure can be toxic. So she and her colleague, OSU cancer researcher Siva Kolluri, began a long search for alternative compounds that would activate the Ah receptor and provide the same benefits as dioxin without the harmful effects. “We had no idea if we would ever find anything that met all our qualifications” Kerkvliet said. They screened several thousand chemicals, spending nearly 2 years until they came across a chemical compound called Cl-BBQ.
“Cl-BBQ has chemical properties that target the same part of the immune system as dioxin does,” Kerkvliet said. But unlike dioxin, Cl-BBQ is quickly metabolized and does not accumulate in the body. They found that Cl-BBQ is most effective when given to mice early in the diabetic process, when some of the insulin-producing cells are still functioning. “In theory, it is during this period that treatment would prevent further loss of cells, and possibly promote regeneration of new insulin-producing cells,” Kerkvliet said.
“It’s gratifying that all the years spent studying dioxins as contaminants have led us to the verge of a new treatment for some very difficult diseases,” she said.