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.
Cancer researcher Siva Kolluri cultivates cells from the most stubborn diseases to find ways to kill them. Recently, he’s discovered that a drug used to treat osteoporosis may also be effective in treating certain breast and liver cancers.
Although clinical trials are still needed, Kolluri’s team found that in lab tests, the drug raloxifene killed human breast cancer cells that are “triple-negative” as well as liver cancer cells. About 15 to 20 percent of all breast cancers in the US are triple negative; these cancers don’t respond to typical medications because their cells lack receptors for hormone proteins.
Receptors are like a lock, and hormones act like keys to unlock different cell functions. For example, estrogen can unlock uncontrolled proliferation of breast cancer cells when bound to a receptor. Raloxifene blocks estrogen from binding to its receptor and thus keeps breast cancer cells from multiplying.
Kolluri’s team has discovered that raloxifene also binds with a protein called the Ah receptor and kills cancer cells that do not have receptors for estrogen. “We discovered that raloxifene, a known drug, could potentially be repurposed to treat two distinct types of cancers,” Kolluri said. “And we can target the Ah receptor and potentially develop new drugs for liver cancer and some stubborn breast cancers.”
The research was funded by the American Cancer Society, National Institute of Environmental Health Sciences, and the US Department of Defense Breast Cancer Research Program. Raloxifene is marketed under the brand name Evista by Eli Lilly and Co.
Flame retardants are chemicals developed to help keep drowsy smokers from going up in flames. They’ve been manufactured into bedding, furniture, cell phones, computer cases, and—up until the 1970s—even children’s pajamas.
Although evidence is scant that flame retardants have prevented fires, evidence is growing that flame retardants are ubiquitous and may be hazardous to health. According to a 2011 University of California study, flame retardants are now found in the blood of up to 97 percent of U.S. residents, 20 times higher than in Europe. Some flame retardants linked to cancer, thyroid disruption, and neurological disorders have been phased out, replaced by new organophosphate compounds whose impact on human health remains unclear.
Kim Anderson is measuring the exposure of preschool children to flame retardants in their homes, schools, and surrounding environments. Anderson, an environmental chemist in OSU’s College of Agricultural Sciences, has pioneered the use of silicone wristbands to assess a person’s exposure to unseen chemicals surrounding us in our daily lives. This study, conducted among 92 3-to-5-year olds in Corvallis and Bend, provided proof of concept for using wristbands as passive samplers with children.
Worn for one week as a bracelet or anklet, the passive sampler goes everywhere the child goes, and absorbs the same chemicals that the child is absorbing. The researchers reported that some children seemed to enjoy wearing the wristbands and called them “their own personal science bracelet.”
Testing the wristbands for 41 flame retardants, the researchers found high levels of polybrominated diphenyl ethers (PBDEs), a group of flame retardants that have been banned in the US for about 10 years. They found even higher levels of organophosphate flame retardants (OPFDs), newer chemistries that replaced the older PBDEs. The researchers were surprised to find some flame retardant chemicals were so saturated in the children’s wristbands that samples exceeded the calibration of the laboratory’s analytic equipment.
Silicone absorbs organic compounds, like your cells do. Anderson and her team have perfected the use of silicone wristbands to passively sample the accumulation of chemicals that an individual encounters daily and to analyze up to 1,400 environmental chemicals recorded in the wristband. By monitoring many chemicals at one time, Anderson’s team is beginning to reveal the chemical environment surrounding children, their parents, and their communities.
