Title: How do parasite products modulate the early events in allergic responses?
Funder: Asthma UK

Abstract: This proposal is to fund research to identify new drugs developed from parasitic worms to prevent or treat allergic asthma. The World Health Organisation estimates there are over 300 million asthma sufferers worldwide, with annual deaths from asthma being estimated at over 250,000 people per year. In populations where parasitic worm infection is common (such as in Africa and South America), the rate of asthma is low. In contrast, in the developed world over the last hundred years parasitic infection has become rare, and over the same time asthma has become far more common. For instance, in Japan, the proportion of the population infected with parasites fell from 15% in 1960 to less than 1% by the 1980s. Over this same time period the proportion of the population with asthma rose from less than 1% to almost 5%. This has led researchers to propose that parasitic infections protect against asthma, and in their absence, we are predisposed to it. Research on the effect parasites have on our immune systems is crucial to unraveling this puzzle. Currently, multiple clinical trials are underway using parasitic infection to suppress disease in people with multiple sclerosis, inflammatory bowel disease and hayfever. However, it is unlikely that parasitic infection will ever be a common treatment for allergic diseases, as not many people want to be infected with parasites, and parasitic infection can cause unpleasant side-effects. Thus it is important to determine how parasites suppress allergic diseases such as asthma, so that we can replicate these effects using a defined product in a pill or injection. Experiments in mice have also shown that parasitic infection potently suppresses pathology in models of asthma, due to inhibition of allergic immune responses. This makes sense for the parasite as the body’s mechanisms that are responsible for asthma also kill parasites, so it is advantageous for the parasite to suppress these. If we can identify how parasites are achieving this, we can then use this information to develop strategies to prevent the development of asthma in children, without requiring infection with parasitic worms In the past, our group has used the mouse parasite Heligmomosoides polygyrus to potently suppress pathology in a mouse model of asthma. We want to now use products released by the parasite to replicate this suppression, so that we can identify which parasite products are responsible, and develop them as therapeutic agents for human disease. We recently showed that products which are either excreted or secreted by Heligmomosoides polygyrus (we call these products “HES”) can replicate the suppression seen with parasitic infection. When HES was injected at the same time as the initiation of asthma, pathology was suppressed weeks later when we tested asthmatic responses. However these experiments used a model of asthma in mice where allergy was provoked by injection of a protein from chicken eggs: this is not a directly clinically relevant model (as humans do not often become asthmatic from inhaling constituents of eggs). Thus we want to replicate these results in models of asthma more relevant to human disease, specifically asthma caused by the moulds Aspergillus and Alternaria, both of which cause severe asthma in humans. Aspergillus and Alternaria are common moulds both indoors and outdoors, and up to 80% of asthmatic patients are allergic to moulds such as these. Mice can also become allergic to these moulds, and in preliminary experiments I have shown suppression of allergic responses when HES was administered with the fungal allergens. I hope to use these models to examine the very early events in the initiation of immune responses that ultimately cause asthma, by seeing how immune cells in the lungs react to fungal allergens, and how this is affected by HES. HES is a mixture of hundreds of different products, so I will then identify which of these products are causing suppression of fu


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM