Jun 28: Immune inhibitory receptors may be a therapeutic target for neutrophil-driven pathologies
The immune inhibitory receptor LAIR-1 (but not Allergin-1) directly inhibits airway-derived neutrophils and limits neutrophilic airway inflammation, suggesting that LAIR-1 has promise as a target for new drugs to treat neutrophil-driven diseases. These findings highlight the functional diversity of inhibitory receptors expressed on the same cell, concludes Ruben Geerdink from UMC Utrecht in his PhD thesis that he defended on June 28, 2023.
The human body is constantly beset by microbes that seek to invade it. To thwart such vile machinations, the body has an intricate collection of cells, organs, and molecules at its disposal, known as the immune system, to protect ourselves. The most abundant immune cell is the so-called neutrophilic granulocyte, or neutrophil. Neutrophils are the immune system’s first responders and are quick to arrive at the site of a potential incursion by a pathogen. In most cases, neutrophils quickly eliminare any would-be invaders. In order to fight infections, the immune system has powerful armaments at its disposal. However, the more powerful the weapons, the more dangerous so-called ‘friendly fire’ becomes. Neutrophils, for instance, can produce and release substances that are lethal to microbes, but these can also cause collateral damage to surrounding tissues. An excessive neutrophil response can therefore do more harm than good. As a result, neutrophils are a driving force behind a plethora of pathologies, varying from viral respiratory infection and ischaemia-reperfusion injury to autoimmune disorders. At current, no medication exists that can supress neutrophils and this represents a significant unmet clinical need. have shown to act as a sort of volume control for the strength of the immune response.
In his PhD thesis, Ruben Geerdink (Center for Translational Immunology, UMC Utrecht) investigated inhibitory immune receptors as possible targets for the development of new therapeutics that dampen excessive neutrophil activity.
Key findings
- Ruben Geerdink and co-workers showed that LAIR-1 directly inhibits airway-derived neutrophils and limits neutrophilic airway inflammation.
- In the same model, they showed that Allergin-1, another inhibitory receptor, fails to control neutrophilic inflammation.
The above findings highlight the functional diversity between inhibitory receptors expressed on the same cell.
Therapeutic target
In this thesis LAIR-1 was identified as a promising target for new drugs to limit neutrophil-driven diseases. Currently, the only drugs that target immune inhibitory receptors aim to block inhibitory signalling. This releases a brake from the immune system that strengthens its response. Known as immune checkpoint blockade it has revolutionized anti-cancer treatment. However, whereas in case of cancer a potent anti-tumor response is needed, in a number of other diseases a softened response from an overeager immune system is called for. In such cases targeting inhibitory receptors in a stimulatory manner may be useful. Therefore, the development of agonists to activate inhibitory receptors may offer an interesting therapeutic approach.The insights from this thesis may contribute to the development of therapeutics that target immune inhibitory receptors to ameliorate, or even cure, therapy-resistant immune-mediated diseases.
PhD defense
Ruben Geerdink (1990, Rotterdam) defended his PhD thesis on June 28, 2023 at Utrecht University. The title of his thesis was “Hit the brakes! – Inhibitory immune receptors as therapeutic target for neutrophil-driven pathologies.” Promotors were prof. dr. Linde Meyaard (Center for translational Immunology, UMC Utrecht) and prof. dr. Louis Bont (Department of Pediatric Infectious Diseases, UMC Utrecht).