Scott Smith, M.D., Ph.D., assistant professor of Medicine, has received a 2017 research award from the Stanley Cohen Innovation Fund to test a new therapeutic strategy for peanut allergies.
The Cohen Fund honors Cohen, Distinguished Professor of Biochemistry, Emeritus and 1986 Nobel laureate, by supporting the type of innovative, high-risk research for which he is known.
“Scott’s project is exactly the kind of research the Cohen Fund is designed to promote — research that tackles really big problems in innovative ways,” said Lawrence Marnett, Ph.D., Dean of Basic Sciences at Vanderbilt University School of Medicine. “Scott’s research has the potential to fundamentally change allergy treatment.”
“It’s an honor to receive this award,” Smith said. “We have developed a new technology that opens up a novel strategy for therapeutic design. The Cohen Fund award gives us the freedom to ask risky, big-picture questions of this new technology.”
The technology enables the production of human IgE antibodies — the proteins that lie at the heart of allergic diseases.
Allergic diseases occur when the immune system overreacts to an allergen, a normally harmless protein found in certain foods, pollen, pet dander and other environmental substances. Allergies are on the rise, with more than 50 million Americans suffering from allergies each year, according to the Centers for Disease Control and Prevention.
In allergic individuals, exposure to an allergen triggers a “type 2” immune response, in which IgE antibodies produced by B cells activate the release of chemical mediators including histamine from specialized immune cells (mast cells, eosinophils and basophils). Histamine and other compounds cause allergy symptoms such as sneezing, runny nose, skin rash and swelling. The most severe reaction, known as anaphylaxis, involves multiple organ systems and can be fatal.
Type 2 immunity evolved to combat parasitic worms, Smith said.
“Parasites are big, mean, multi-cellular organisms, and type 2 immunity has to be extremely powerful to attempt to kill them,” he said.
In developed countries, however, fewer people are exposed to parasitic worms.
“As our living environments have become cleaner, and we have less exposure to outdoor organisms, we’re not teaching our immune systems what’s good and what’s bad,” Smith said. “This is the crux of the ‘hygiene hypothesis’ for allergic disease. Our anti-parasite immunity is now misfiring against innocuous proteins in our environment.”
To develop new strategies for treating allergic diseases, it is crucial to explore the interaction of IgE antibodies with the specific allergens they recognize, Smith said. But IgE antibodies have been elusive, until now.
Smith’s laboratory is the first in the world to produce allergen-specific human IgE monoclonal antibodies.
Smith relied on expertise he developed during his years as a research fellow at Vanderbilt, where he generated numerous IgG-type monoclonal antibodies against viruses. IgG antibodies are part of “type 1 immunity;” they are the “good antibodies” that are used therapeutically for cancer, rheumatologic and other diseases,” Smith said.
To produce IgE monoclonal antibodies, Smith and his colleagues used blood from patients with severe allergies, isolated B cells that produce IgE antibodies, and fused the B cells with myeloma (cancer) cells to form “hybridomas.” Each unique hybridoma secretes human IgE monoclonal antibodies that are specific for a certain allergen. Smith and his colleagues have produced more than 250 different allergen-specific IgE monoclonal antibodies.
For the Cohen Fund award, the researchers will focus on peanut allergies.
“We’ve made a panel of peanut-specific IgE monoclonal antibodies from patients that have severe reactions to peanut,” Smith said. “These are the antibodies that will kill these patients if they consume peanuts.”
Now, the researchers will attempt to turn the pathogenic IgE antibodies into therapeutic IgG antibodies. They will use the IgE genetic sequence in a recombinant expression system to produce IgG antibodies that will theoretically bind to the peanut allergens and prevent the pathogenic IgE antibodies from binding.
They will test the potency of the peanut-specific IgG therapeutic antibodies against allergic patients’ serum using standard allergy assays, and they will explore the function of the therapeutic antibodies in mouse models of peanut-induced anaphylaxis.
“It’s complicated because it’s pretty technical, but it revolves around the fact that we’re the first lab in the world to ever be able to obtain these molecular tools,” Smith said. “Having these tools allows us to pursue an entirely new therapeutic strategy to attempt to cure people of allergy.”
