Finding an end to allergy
When Dr. Christine McCusker was 8 years old, her brother, who had a crush on Raquel Welsh, tuned into a television rerun of the 1966 movie Fantastic Voyage. She watched it with him. In the film, a miniaturized vessel, complete with a crew, travels through an ailing scientist’s circulatory system to perform a lifesaving, clot-busting operation. At the climax, immune-system antibodies attack the villain and a giant macrophage consumes the ship.
“That the body could do that was the coolest thing ever,” she says. “Immunology rocks!”
She’s still a believer. Her fascination with the immune system has led to groundbreaking work that may revolutionize treatment of asthma and allergy. One day, it may even prevent these diseases.
McCusker is at the forefront of research into asthma and allergy vaccines that attack the early stages of an allergic response to pollen, peanuts and other substances.
To pursue her passion, she obtained a degree in microbiology and immunology at the University of Toronto and earned a Masters at McMaster University. Her PhD studies focused on immunogenetics in the HLA system, i.e., what happens when the immune system doesn’t work. She spent 5 years in immunology research before entering medical school to become a pediatrician.
During her residency at McGill University, Bruce Mazer, chief of allergy and immunology, learned of her background in immunology. He encouraged her to apply for a fellowship that would combine her expertise in immunology with clinical allergy and asthma. Her post-doc studies in his lab formed the basis of her work on what happens in the immune system of newborns with allergy and asthma.
Research at her Meakins-Christie laboratory at McGill has shown that greater exposure to potential environmental allergens early in life aids the development of tolerance in newborn mice. “Clean” environments tend to promote allergic responses to these harmless substances.
Normal vs allergic responses
Humans are exposed to millions of microbes, particulates and other natural substances in our environment daily. Normally, the immune system learns to tolerate harmless proteins.
However, if a protein exhibits suspicious traits, such as a distinctive surface pattern or rapid growth in size or number, the immune system identifies it as a harmful invader and kicks into high gear.
In people who develop allergies, the immune system misidentifies harmless proteins as harmful. Instead of tolerating them, it sounds an intruder alert that triggers an allergic response.
A cascade of intercellular signals between different immune cells tightly controls this response. McCusker and colleague Dr. Elizabeth Fixman wondered what would happen if they interfered early in the signalling process.
Fixman developed an inhibitory peptide (IP) that switches off a transcription factor called STAT-6 inside T helper-2 (TH-2) cells. These immune cells play a key role in recognizing new environmental proteins. When a new protein enters the body, dendritic cells capture samples and present them to TH-2 cells for identification.
TH-2 cells may, in fact, drive the allergic response. “They are a central piece of the puzzle,” says McCusker.
When allergic mice were treated with STAT-6-IP, they developed no asthma symptoms.
“We actually blocked the allergic response really well,” says McCusker, now Associate Professor of Pediatrics at McGill and Director of the Division of Allergy and Immunology at the Montreal Children’s Hospital of the McGill University Health Centre, Montreal, QC.
“In subsequent experiments, I’ve shown that this blockage can last for fairly long periods in allergic mice before (immune-system) memory returns.”
When the immune system encounters a familiar protein, it remembers its first response. “That’s why, once allergy or asthma develops, we talk about control, not cure,” she explains. “We want to see if, with repeated treatment, we can actually drive the immune system in another direction.”
McCusker hopes that STAT-6-IP will lull TH-2 cells to sleep at their posts, silencing false warning signals. When that happens, over time, “all clear” signals from co-stimulatory immune cells may reprogram the immune system to tolerate former allergens.
“The fun part about working with the immune system is that it isn’t a fixed thing. It changes every day. With every new encounter, it learns and modifies what it does. It’s a forward-looking system.”
Vaccine to prevent asthma in newborns?
The STAT-6-IP results in mice with asthma raised an important question: if allergy-prone mice were treated before their immune system developed memories of intolerance, could STAT-6-IP prevent allergens from awakening the TH-2 response?
To test the hypothesis, McCusker and her team treated 3-day-old, allergy-prone mice with STAT-6-IP nasal drops once daily for 5 days. Much later, during adolescence, the researchers exposed the mice to two common allergens: egg albumin and ragweed pollen.
“No matter what we did, no matter how aggressively we tried, we could not make these animals allergic,” says McCusker, who is also a scientist from the Translational Research in Respiratory Diseases Program at the Research Institute of the MUHC.
“We later showed that, in treated mice, these allergens were presented to TH-2 cells with the profile of costimulatory molecules that were driving tolerance. Basically, the immune system remembered that innocuous proteins should be tolerated,” she says.
“We call this process immuno-modulation or immuno-education.”
The treatment did not completely silence TH-2 cells, because McCusker and her coworkers witnessed normal immune responses when the mice where exposed to microbes, such as bacteria and viruses. In fact, they showed that STAT-6-IP-treated, allergy-prone mice infected with flu virus actually fared better than untreated animals.
STAT-6-IP stays in the body for less than 12 hours. “We gave it to the mice for 5 days, and it was gone by day 6,” she says, “But the memory was there. That’s awesome immunology.”
Her current research is exploring how allergy-prone mice respond to peanut allergens after early STAT-6-IP treatment. Her next step is to determine whether STAT-6-IP can influence immune responses in blood samples from people with allergy or asthma.
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