Asthma and respiratory allergies: a promising new therapeutic target

Summary

Allergic asthma is a chronic inflammatory disease that affects millions of people worldwide. Despite effective treatments to control symptoms, there is still no curative treatment.

French researchers have identified a molecule so far little studied in asthma: TL1A, a protein released very early upon contact with an allergen. This discovery opens the way to the development of new biological treatments capable of acting from the very first stages of the allergic reaction.

What is allergic asthma?

Asthma is a chronic disease characterised by inflammation of the bronchi. In people with allergic asthma, this inflammation is triggered by allergens such as:

• pollens;
• dust mites;
• moulds;
• animal hair;
• certain microscopic fungi.

When an allergen is inhaled, the immune system overreacts, causing:

• a contraction of the bronchial muscles;
• excessive mucus production;
• swelling of the bronchial wall.

This combination leads to the characteristic symptoms: shortness of breath, wheezing, chest tightness and cough.

Why are current treatments not always enough?

The treatments available today generally make it possible to control the disease. They are mainly based on:

• inhaled corticosteroids;
• bronchodilators;
• certain biological treatments targeting IgE, IL-5 or IL-4/IL-13 in severe forms.

However, some patients have severe asthma that remains insufficiently controlled despite these treatments. It is precisely for these patients that new approaches are being sought.

A new molecule identified: TL1A

The French researchers focused on a protein called TL1A. This molecule belongs to a family of proteins nicknamed alarmins. As their name suggests, they act as an alarm signal.

When the cells lining the bronchi detect an allergen, they quickly release these molecules to alert the immune system.

How does an allergic reaction begin?

The study shows that just a few minutes after exposure to an allergen, the cells of the airways simultaneously release two alarmins:

• TL1A;
• IL-33.

These two molecules then activate a particular type of immune cell called ILC2 (type 2 innate lymphoid cells). These cells then produce several inflammatory substances, in particular interleukins such as IL-5, IL-13 and IL-9, which sustain the allergic reaction.

The result is inflammation of the bronchi responsible for the symptoms of asthma.

Why is this discovery important?

Most current treatments act after inflammation has been triggered. TL1A intervenes much earlier. By blocking this molecule, it could become possible to interrupt the inflammatory cascade at its very origin.

In other words, instead of treating the consequences of the allergic reaction, it could be possible to act on its triggering.

Antibodies are already available

One of the most encouraging aspects of this discovery is that antibodies directed against TL1A already exist. They were developed to treat certain chronic inflammatory diseases, in particular Crohn's disease.

These treatments could therefore be evaluated more quickly in patients with severe asthma, without starting from scratch.

An increasingly personalised medicine

Not all asthma patients have the same immune mechanisms. In the future, it will probably be possible to determine which patients have significant TL1A activation and to offer them a specifically targeted treatment.

This approach is fully in line with the development of personalised medicine.

An avenue for COPD too

The researchers believe that this discovery could also benefit other inflammatory lung diseases. This is particularly the case for chronic obstructive pulmonary disease (COPD), a disease often linked to smoking and characterised by chronic inflammation of the airways.

Clinical trials are already being considered.

What are the limitations of this study?

Despite its interest, this discovery remains a research step. The study demonstrates the role of TL1A in inflammatory mechanisms, but it does not yet prove that an anti-TL1A treatment will effectively improve asthma in all patients.

Clinical trials will be essential to confirm:

• efficacy;
• safety;
• the patients likely to benefit.

What this study does not demonstrate

This study does not show that:

• a curative treatment for asthma is available;
• all asthmatics will benefit from an anti-TL1A;
• current treatments can be replaced soon.

It identifies a very promising therapeutic target that will now have to be validated in humans.

The Valorian analysis

This study represents an important advance in our understanding of the first stages of allergic inflammation. By identifying TL1A as a key alarmin alongside IL-33, the researchers open the way to a new generation of targeted treatments, capable of intervening before the inflammatory reaction fully sets in.

The interest of this discovery also lies in its potential for rapid transfer to clinical practice. Unlike many still-theoretical therapeutic targets, anti-TL1A antibodies are already in development for other inflammatory diseases, which could speed up their evaluation in severe asthma.

At Valorian, we consider this research to be an excellent example of precision medicine. The future of treating allergic diseases will probably no longer rely on a single approach for all patients, but on therapies adapted to each person's immunological profile. Antibodies targeting alarmins could, in the coming years, complement the biotherapies already available and improve the management of the forms of asthma that are hardest to control.