Professor Franca Ronchese, Immune Cell Biology programme leader.

Allergy Today: Research finding may lead to new asthma treatments

19 April 2018, Allergies, Immune Cell Biology, Professor Franca Ronchese

This article originally appeared in Autumn 2018 issue of Allergy Today

Professor Franca Ronchese and her team at the Malaghan Institute find a new role for an old molecule in the fight against allergic disease.

In the world of immunology and allergy, we know the players — the cells, chemical signals and molecules — but we’re still trying to understand the game. What causes the immune system to attack one person's body but defend another’s? We can quantify the effects, but we don’t yet know all the causes.

To complicate things further, we’re constantly finding new ways in which molecules and cells interact with each other, which means we need to shift our understanding of them each time we do. While this may seem frustrating when trying to determine what causes something like a peanut allergy, the upside is that new discoveries offer tantalising opportunities for innovative new treatments and therapies.

Recently, HRC-funded research at the Malaghan Institute uncovered a new role a key molecule plays in the development of the allergic response. For people suffering from allergic disease such as asthma, this discovery could one day lead to new treatment options.

The molecule, thymic stromal lymphopoietin (TSLP), is made by epithelial cells, such as those in the outer layer of our skin, or in our airway and gut, when they are exposed to damage. This could be from a trauma or infection, or through coming into contact with an allergen. TSLP has several roles, one of which is keeping T helper 2 (Th2) immune cells alive. However, Professor Franca Ronchese and her team have found that TSLP also plays an important role in their early development.

Immune cells like Th2 help regulate the immune system, and for most of us, they do their job well. However, in the case of allergic diseases, the Th2 cells cause more harm than good — causing inflammation when they come across harmless triggers such as pollen, house dust or a peanut.

“For people with inflammatory conditions such as asthma and allergies, Th2 cells are responsible for making a number of factors or molecules that cause inflammation and they can signal other cells to do the same. In the case of asthma, this excess inflammation can cause damage to airways and the typical shortness of breath experienced by asthma sufferers,” says Professor Ronchese.

Observation provides important clue

But what causes Th2 cells to do this remains largely a mystery. A mystery, that seems to lie in the way the cell develops.

“What is not yet completely clear is how those Th2 cells that we find in the lung or the skin or the gut develop. When we look at the early stages of the immune response, Th2 cells look different and don’t really produce any of these inflammatory molecules. Somehow, they then change — learning to cause inflammation and tissue damage.”

This is when the molecule TSLP was seen, quite accidentally, to have an important secondary effect.

“It started with an observation. We found that in some conditions where there is a lot of TSLP, Th2 cells develop very quickly during an immune response. With further research, we found that TSLP was turning on the cells that can cause inflammation in tissues.

“People thought that TSLP acts mainly in later stages of the immune response, and maybe only in the lung and the skin. We’re saying no, it can act much earlier than that and really drive these cells to become inflammatory from the start.”

The discovery of TSLP’s earlier role is giving Professor Ronchese and her team important clues about how the immune system game is being played. Importantly, it suggests that there may be exciting opportunities to target TLSP in therapies — preventing it from developing cells that cause damaging inflammation in allergy sufferers. Indeed, new drugs that target TSLP are being tested in early clinical trials, and they have been found effective in patients with moderate-to-severe asthma. The recent studies at the Malaghan Institute help explain why this is.

Results of the clinical trial were published in N Engl J Med 2017;377:936-46.