Under the skin: Canadian research targets allergic reactions

Innovative engineered biomaterials disrupt allergic reactions

Imagine being prepped for surgery and then finding out you’re allergic to the anesthetic. What if antibiotics or antidepressants give you a rash? Or a bee sting sends you into anaphylactic shock?

Allergies impair quality of life and take a toll on economies and personal budgets. The number of allergic diseases is on the rise, with triggers lurking around in the air, in food and beverages, and in products such as cosmetics and clothing.

Foreseeing allergies, identifying their sources and creating solutions is a daunting task. Even though allergic reactions are common—particularly to drugs and neuromuscular blockers used during surgery—many cannot be explained, anticipated or treated. Allergies are most often triggered when a patient forms antibodies to allergens like pollen, cat dander or medications. The body confuses these normally innocuous substances with dangerous ones and targets them with an immune response.

Medical diagnoses are based on the presence of such antibodies in a patient’s blood. However, allergic reactions are sometimes triggered without these allergen-specific antibodies, so the cause of the response is not easy to identify. This condition is sometimes called a pseudo-allergy.

The cause of these pseudo-allergies is a receptor called MRGPRX2, which lives on mast cells and can be activated by various allergens. Mast cells, which inhabit the skin, lungs and intestines, store little pockets of histamine—a chemical that triggers other cells to cause swelling, itching, redness and tightening of the airways. Mrgpr activates mast cells to release histamine.

“Understanding how mast cells and Mrgprs operate is an important step toward countering common problems like mast cell disorders and uncontrollable inflammatory responses,” says Marianna Kulka, Biomedical Nanotechnologies Team Lead at the National Research Council of Canada (NRC). “We also believe that finding an inhibitor that blocks Mrgpr activation could be beneficial to treating a range of other situations including wound healing, antibiotic resistance and bacterial infections.”

Research gets under the skin

In 2014, Kulka and a team of colleagues at the NRC and the University of Alberta (U of A) confirmed this particular function of MRGPRX2, which had been discovered by Ben McNeil, assistant professor at Northwestern University in Chicago. He had used his animal model systems to show that the receptor was important in activating pseudo-allergic reactions. This collaboration was the first research in the world to show how MRGPRX2 responds to protein activators and why it’s important on mast cells.

The next phase of the research is clinical trials, which will be aided by another of McNeil’s discoveries. “I developed a way to screen drugs to see if they activate this receptor,” he says. This means companies can predict whether certain medications will cause pseudo-allergic reactions in humans before they embark on clinical trials.

While unregulated mast cell activation can be damaging to the body, the cells also alert the immune system to invaders and regulate wound repair once they have breached the skin, lungs or intestines. A localized and precisely controlled process of mast cell activation may benefit the body by enhancing the clearance of infectious organisms and accelerating skin healing.

While Kulka was examining how the receptors might activate allergic inflammation, a team led by Larry Unsworth, U of A professor, Chemical and Materials Engineering, was working on self-assembled nanomaterials that could be functionalized for this purpose.

Kulka reports that by using Unsworth’s material designs and the NRC’s cell culture system, they discovered that the receptor influenced mast cell activation as well as inflammatory reactions, which can be beneficial when an immune response is necessary to flag infections or skin damage. They were then able to move their analysis onto human skin cells supplied by a clinical researcher. “This is as close as you can get to human testing, so it sped up our research considerably,” adds Unsworth.

According to Unsworth, these extended studies have had a high impact on the field of immunology. “With Marianna’s expertise in cell biology and mine in molecular design, we devised a topical hydrogel, or tissue-engineering scaffold, that activates mast cells only on the affected area of the skin—and may use human cells to ultimately repair tissue.”

Promoting disruptive thinking

The published findings of the NRC and U of A teams generated a great deal of attention from around the globe. Their papers have been cited often, and the receptor generated considerable interest. It has also led to investigations into broader uses, particularly inflammatory diseases.

“Many conditions, especially age-related diseases, have inflammatory conditions as an underlying pathology, so we must understand these different types of inflammation and how they progress as we age,” says Kulka.

By giving its researchers the freedom to explore different areas, the NRC opens the doors to creativity in disruptive technologies. Kulka also appreciates the NRC’s flexibility in allowing scientists like her to have adjunct appointments at universities and to work with research organizations around the world—even take sabbaticals to focus on projects.

“These studies are great illustrations of cross-disciplinary collaboration that has not only met everyone’s fundamental research goals, but also created tremendous synergies that have led to new discoveries,” says Unsworth. “And that is a good thing for Canada and the world.”