Epidermal growth factor receptor antagonists: Effect on regulatory T cells, and use as an adjuvant treatment for infectious disease

Epidermal growth factor receptor (EGFR) is a protein present on the surface of several human body cells, and some white blood cells. When it is activated it triggers cells to grow and change their function. Recently, our group has discovered that regulatory white blood cells (WBC), which
reduce inflammation, respond to EGFR signals. Our aims are to see if by blocking this signal, we can stop regulatory WBCs from being activated, so improving the bodys immune response (i.e. its ability to recognise & fight infection).

If regulatory WBCs can be manipulated in this way, then we may be able to use EGFR-blocking drugs to improve the immune response to infection/immunisation. We will study this using a drug that blocks EGFR. We will use a chronic worm infection of mice, as they activate regulatory WBCs to promote their own survival. We will then examine the effect of EGFR signals on a commonly used virus vaccine to see if the immune response to vaccination can be improved by blocking EGFR.

Infectious diseases are a major burden to mankind and new approaches to treat infections as well as enhance vaccination efficiency are urgently required. The immunosuppressive effect of FoxP3 expressing regulatory T-cells (Tregs) is a substantial hurdle in the induction of protective immune responses, and diminishing Treg activity would be an exciting potential novel immunotherapy. It has recently been shown that Tregs are dependent on Epidermal Growth Factor Receptor (EGFR) signalling for optimal function, and that Tregs show diminished suppressive capacity during the therapeutic application of EGFR-inhibitors. This project aims to establish whether reduced Treg activity (by EGFR-blockade) enhances pathogen-specific immune responses during infection and vaccination.

Infected mice will be treated with the EGFR-specific tyrosine kinase inhibitor Gefitinib, a drug already in wide clinical application. To test whether EGFR inhibition can induce pathogen clearance, a Litomosoides sigmodontis infection model will be used. For this chronic helminth infection it is established that Treg-function prevents pathogen clearance. In parallel, to test whether EGFR inhibition can enhance the efficacy of immunization, We will examine the effect on vaccination response using the Modified Vaccinia Ankara-Ovalbumin model. MVA contains an EGFR ligand, which we will attempt to delete to increase vaccine efficacy.

Infectious disease continues to exert a large burden of disease on resource-poor countries, and threatens to make a significant impact on developed countries in the post-antibiotic era. As well as mortality, many diseases (notably helminth worms) have a significant morbidity impact. Developing new therapies for diagnosis and treatment of infections has received significant attention in recent years as the risk to the general population continues to increase.

This research focuses on the modification of a host-pathogen interaction to improve disease outcomes. It is expected that the impact will initially focus on those already studying regulatory T cells, helminthic disease and the use of MVA as a vaccine vector, both in academia and the pharmaceutical industry.

Both aims of the project have a 'line of sight' to improving outcomes for patients in the long-term, either by enhancing immunity against macroparasites (using a biological agent that is already in clinical use) or by improving the efficacy of MVA as a vaccine vector. These developments would be of obvious benefit in a post-antibiotic era, and have the potential to alter the treatment of infectious disease in resource-poor countries, where the greatest burden lies.