Punching holes in dendritic cells - could this be the key to controlling asthma?
Asthma remains one of the most prevalent allergic diseases in the world. It is a chronic inflammatory disease of the airways, characterised by wheezing, coughing, chest tightness and shortness of breath.
Specialised white blood cells called Th2 T cells are known to play an essential role in the pathogenesis of asthma. They are activated by immune cells called dendritic cells (DC) in response to harmless environmental allergens such as house dust mites or pollen. Once activated, the Th2 T cells release cytokine proteins, which recruit inflammatory cells into the airways, causing asthma.
One of the most puzzling things about allergic diseases is that different people react in different ways. While particular tree pollens might stimulate the allergic Th2 pathway in some individuals, causing them to develop hay fever or asthma, others will be completely unaffected by them.
The steroid inhalers that are currently used to treat asthma work by reducing the airway inflammation so it is easier to breathe. Although effective at relieving the downstream symptoms of asthma, they do not treat the actual cause of the disease and their non-specific mechanism of action can leave users more susceptible to common infections such as influenza.
Malaghan Institute scientists believe that a more effective approach would be to stop the asthma pathway by targeting therapies against the dendritic cells that are responsible for activating the disease-causing Th2 T cells.
Previous work at the Malaghan Institute and other laboratories had shown that activating another class of T cells called cytotoxic T lymphocytes, or CTLs, prevented the development of airway inflammation. However, the mechanism used by the CTLs to suppress disease was still unclear.
We know that killing by CTLs is important for rejecting tumours and for eradicating cells infected with viruses, but the importance of killing in controlling asthma and allergy has not really been considered, says Prof Franca Ronchese.
With the support of the Health Research Council of New Zealand, Dr Noriyuki Enomoto and Prof Ronchese (pictured above) undertook further research to determine how the CTLs were able to stop airway inflammation, and they discovered that this phenomenon was dependent on their ability to release a protein called perforin.
Perforin is a protein found in the granules of CTLs. Upon its release, perforin inserts itself into the membrane of a target cell, forming a pore. This sets off a pathway that leads to the cells death.
Prof Ronchese and colleagues used several different approaches to show that if the CTLs were unable to release perforin, they were unable to prevent the development of acute asthma. Their results, which have just been published in the international Journal of Immunology, also indicated that the likely target of the CTLs killing activity were the airway dendritic cells.
Our work has revealed a previously unappreciated mechanism for CTL regulation of the immune response, which may be relevant to the pathogenesis of allergic asthma, says Prof Ronchese. We believe that activated CTLs can kill allergen-presenting dendritic cells in the airways by effectively punching holes in them.
With fewer dendritic cells around to activate the disease-mediating Th2 cells in the airways, there is consequently less allergic airway inflammation.
The above work was undertaken using an acute model of allergic asthma. Prof Roncheses research team is now developing a more clinically relevant chronic model of asthma to investigate the potential of exploiting CTL activity for the treatment of individuals with established allergic airway inflammation.
Unlike steroid treatment, immune therapies that use allergen-specific CTL are not expected to be broadly immunosuppressive, and may lead to improved treatments for asthma and other allergic diseases, says Prof Ronchese.
This work was supported by a research grant from the Health Research Council of New Zealand and infrastructure funding from the Maurice Wilkins Centre of Research Excellence.
Enomoto, N, Hyde E, Zhi-Iong Ma J, Yang, J, Forbes-Blom E, Delahunt, B, Le Gros G, Ronchese F (2012) Allergen-specific CTL require perforin expression to suppress allergic airway inflammation. J Immunol, 188: 1734-41
Link to Pubmed abstract