Research Profile – Immune Overkill

Laval researchers study the role of dysfunctional immune cells in asthma.

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Over 2.4 million Canadians suffer from asthma. It can cause permanent changes in the shape of the lungs, disability, and even death. Yet there are still many asthmatics who do not respond to current therapies.

Now, researchers in Quebec have uncovered details about the mechanisms underlying the disease. Their paradigm-shifting findings could lead to the development of new treatment strategies, as well as greater understanding of how asthma leads to tissue damage in the lungs.

The research, supported by the Canadian Institutes of Health Research, focuses on a type of immune cell found in the lung – alveolar macrophages. According to Dr. Elyse Bissonnette, a professor of immunology at Laval University, macrophages are the main type of immune cell found in the lung.

Macrophages are a type of white blood cell that engulfs foreign material such as bacteria or cellular debris and digests or breaks it apart. While they play an active role in protecting the lungs from infections, they also stimulate other parts of the immune system into action when more support is needed to fight an infection.

"We think that in asthma, these macrophages are dysfunctional," she said. In fact, research suggests they play a far greater role in the inflammation and hyper-reactivity seen in asthmatic lung tissue during an asthma attack than previously suspected.

In standard models of allergic asthma, different types of immune cells are portrayed as the key culprits: mast cells, eosinophils and T cells. It is believed that in asthma, mast cells are overly active and cause too much inflammation in the lungs. Inflammation is a hallmark of asthma, and leads to airways becoming constricted so asthmatics cannot breathe properly.

In this older model, macrophages were viewed as a minor player, Dr. Bissonnette says. But research from her lab suggests dysfunctional macrophages play a far more important role in allergic asthma (asthma that is triggered by a specific allergen).

In one experiment, the researchers studied a group of rats that were asthma-free and a group that had allergic asthma. Researchers found that the asthmatic rats had dysfunctional macrophages in their lungs that did not protect against asthma symptoms. Researchers then gave the healthy rats a compound that destroyed most of the macrophages in their lungs and found that those rats then showed asthma symptoms too. So, a lack of functional macrophages appeared to trigger symptoms.

In a second experiment, researchers depleted the dysfunctional macrophages in the lungs of the asthmatic rats then replaced them with healthy macrophages. Doing this "actually protected the animals against asthma symptoms. Now what we're trying to understand is how that works," Dr. Bissonnette says.

Research in Dr. Bissonnette's laboratory also suggests it may be possible to 'reset' dysfunctional macrophages into working ones.

The researchers grew two sets of macrophages in the lab: one in which the macrophages were treated with different compounds to see if any of them made the macrophages less dysfunctional. In the second set, nothing special was done – these were used as a control set.

To the researchers' surprise, when control macrophages were put back into the lungs of asthmatic rats – the asthma symptoms in the rats were reduced.

"These [untreated] macrophages protected the animals. Just by keeping the alveolar macrophages from an asthmatic rat in culture for 24 hours, and then putting them back in the animal, that protects the animal. This means alveolar macrophages can be reprogrammed to protect," she says.

It is unclear if this protective effect is a short-term or long-term. It's possible there is something else about the asthmatic lung that triggers the macrophages to become dysfunctional. Eventually, the goal is to find better therapies for people, but it will still take a number of years and more work in the lab to get to that point.

"We think that in asthma, these macrophages are dysfunctional."
– Dr. Elyse Bissonnette, Laval University