Altering cellular function of immune system could help target allergies

Peanut allergy has long-term consequences and potentially life threatening effects, but there is no clinically available cure. A cellular and molecular could provide new clues.

Building on over 20 years of research in immunology, experts at Bristol University are now looking at novel ways to provide a more detailed understanding of allergies from a cellular and molecular perspective.

Ever since Leonard Noon first discovered that allergen-specific immunotherapy could be used to desensitise allergy sufferers by exposing them to increasing doses of the antigen, therapeutic interventions have focused on improving tolerance. However, despite Noon’s discovery in 1911, strict avoidance remains the only option for sufferers of some of the more severe allergies, including allergy to peanut, which affects between 200,000 and 400,000 people in the UK and around three million in the US.

“One of the major reasons that no curative treatment yet exists is because the immunological principles behind allergic sensitisation and therapeutic desensitisation are poorly understood,” explains Dr Johan Verhagen, an expert on immune regulation in both allergy and autoimmune disease in Bristol University’s School of Cellular and Molecular Medicine. “Given the increasing number of people affected by allergic disorders and the steady increase in their prevalence, a better understanding of the immunological principles underlying the condition will benefit a large proportion of the population.”

Thanks to seed funding from the Elizabeth Blackwell Institute for Health Research (EBI) Dr Verhagen, alongside laboratory technician Ella Shepard, is working towards establishing an independent lab and they are currently developing the ideal animal models that will enable them to investigate the functionality of a series of interrelated cells in the immune system. They hope to discover how the mechanisms of these cells could be manipulated to maintain and restore a balanced response to common environmental antigens, thereby providing a more targeted approach to improving immunity.

Allergic reactions are often the result of a lack of adequate T cell regulation. Specialised regulatory T cells, which serve to protect the body against both external and internal antigens, will be the core focus of this study.

While at the Swiss Institute of Allergy and Asthma Research, Dr Verhagen was part of the team that proved the importance of maintaining a balance between T regulatory cells and conventional, pro-inflammatory, T cells for a healthy response to potential allergens. Those findings were published in the Journal of Experimental Medicine in 2004. Subsequent studies have further demonstrated the role of IL-10 secreting cells and inducible FoxP3 cells – both subsets of Treg cells – in the healthy functioning of the immune system.

IL-10 secreting cells can be generated by repetitive administration of relatively large quantities of an antigen. FoxP3 cells offer a solution that is potentially even more viable as they can be generated using a lower dose of the antigen. The study will therefore seek to identify the optimal antigen-specific method to generate these subsets of Treg cells in a model of peanut allergy.

“My recent work, and that of others in the laboratory of Prof David Wraith, has demonstrated how we can generate these subsets of T regulatory cells in models of autoimmune disease and thereby create a healthy immune balance”, explains Dr Verhagen. “The challenge now is to translate this knowledge into a novel and improved immunotherapy for allergic disease.”

While confident in their hypothesis, Dr Verhagen and Miss Shepard caution against the tempting assumption that it will lead to an immediate cure for allergy sufferers, least of all because of the necessarily lengthy and rigorous pace of research, which can take many years to reach the stage of clinical trials, and for trials to then yield conclusive results.

Miss Shepard adds: “Some of the work that informs how we are approaching this goes back 25 years. All the components from various research projects to date add up to create a bigger picture, which we’re trying to apply to a different setting. Each stage of it combines so it’s not possible to say that one result will lead to a cure. It doesn’t mean that it isn’t possible, just that a lot of components have to come together. However, we are in a good position, in that we have the knowledge of several different labs that contribute to this effort.”

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