Asthma & Parasitic Diseases Group Current Research

Project One: The Basic Biology of the Th2 Response

Our Asthma Research Group passionately believes that greater knowledge of the basic biology of the Th2 immune response is required before we can realistically start to provide practical advice on how best to avoid asthma and allergy.

The two immune cell types of particular interest to us are basophils and dendritic cells (DCs). We have shown that basophils are a principal source of IL-4 production and are currently examining the role they play in the induction of Th2 immunity in vivo. We are also investigating the contribution of DCs to the pathogenesis of allergic asthma using the drug FTY720, which blocks DC migration.

In 2007 we provoked much international discussion by demonstrating that IL-4 and STAT6 were not required for Th2 development in our asthma and allergy models. We have now extended this work by showing that IL-2 levels, which are thought to be responsible for activating and expanding T regulatory cells, increase in the absence of STAT6. The significance of this finding with respect to the development of a Th2 immune response is currently being investigated.

This groundbreaking work is providing new insight into the allergic disease process and we look forward to applying this information to the development of new diagnostic drugs and assays in the coming years.

Project Two: Bringing together, Parasites, Dust Mites and the Th2 Response

Two billion people worldwide are infected with intestinal nematodes such as hookworms, which can cause intestinal blood loss, protein malnutrition and anaemia.

Using the harmless laboratory-adapted rodent nematode Nippostrongylus brasiliensis, which has similarities to human hookworm and provokes immune responses reminiscent of asthma, we have shown that the lung is a central site for inducing protection against re-infection. In 2007 we discovered that the first point of contact of the worm to the host, the skin, is not as important as first thought. By tracking the different stages of the parasite as it migrates through the host, we have also been able to gain valuable insight into the location of the priming and cellular immune responses to the parasite allergens. This vital information will assist in the development of vaccination strategies against these parasites.

Last year we developed a novel Ear Model to measure the early induction of a Th2 immune response. In collaboration with Assoc Prof Jeroen Douwes and Prof Neil Pearce from Massey University, we are now using this model to measure the immune responses to environmental allergens known to trigger asthma such as house dust mites, pet dander and cockroaches. The results of this work will help us to identify the critical cells to target to halt an asthmatic reaction.

Project Three: A Sweet Solution to Asthma

While much is known about the causes of asthma, few studies have looked at the molecular structures of the allergens that trigger the disease and the role they play in influencing Th2 immune responses. In 2007 Dr Bridget Stocker, a resident synthetic chemist overseeing the Immunoglycomics research at the Malaghan Institute, was successful in securing funding that will enable us to address these key questions.

Upon close examination of the structural features of allergens such as pollen, food, and worms, we observed that particular structures (N-glycans) were conserved. Interestingly, antigens derived from bacteria and viruses neither possess these carbohydrate structures nor stimulate allergic immune responses, leading us to hypothesise that these unique structural motifs might be responsible for biasing the immune response towards Th2.

To investigate this hypothesis we will synthesise a library of N-glycans and test them in several Th2 immune response assays.

We hope that these studies will provide the first detailed insight into the relationship between N-glycan structure and Th2 bias and will lead to a better understanding of allergy and asthma.

Clinical Relevance and Future Direction

Asthma is a debilitating disease of major concern to our community. Our research programme is providing much needed information for the development of effective ways to treat this disease. We hope that by understanding how worm allergens stimulate the allergic Th2 immune response we will in turn learn why harmless environmental allergens can inadvertently trigger this same response. It is hoped that knowledge of such principals will aid in the design of new therapies for allergy and asthma.

A significant flip-side to our research is the identification of more effective ways to treat parasitic worm diseases. The harmless laboratory-adapted nematode we use in our studies of worm infection has similarities to parasitic worms that cause disease in humans such as the hookworm parasite. Consequently we hope to be able to use our research to make an effective vaccine that can be used to treat the many devastating parasitic worm diseases affecting humans around the world.

Collaborators

Prof Rick Maizels, University of Edinburgh, UK
Dr Kathy McCoy, University of Zurich, Switzerland
Dr Booki Min, Cleveland Clinic, USA
Dr William Paul, NIAID, National Institutes of Health, Washington DC, USA
Prof Neil Pearce and Assoc Prof Jeroen Douwes, Centre for Public Health Research, Massey University, Wellington, New Zealand
Prof Murray Selkirk, University College London, UK

Other relevant progress

The where, why, and how of the asthma -causing TH2 cells

Our first focus has been to try and follow how the asthma-causing Th2 cells recirculate through the body and establish how it is that they migrate to the lungs and remain there for so long causing disease. One difficulty in performing this research is that the Th2 cell is very rare (less than 1% of T cells) and induces asthma symptoms very rapidly, making it extremely difficult to study and measure.

An important new tool for boosting this research has been provided through collaboration with Dr William Paul at the National Institutes of Health, Bethesda, USA.  Dr Paul has genetically engineered asthma-causing Th2 cells, which fluoresce (glow) whenever they start to stimulate asthma-like symptoms. We are now able to track and follow the behaviour of this key cell in lung tissue. Already very significant findings are emerging from our studies; it would seem that lung resident Th2 cells are quite different from those found in lymph nodes or blood. Some of these differences could go some way to explaining just why some forms of asthma are difficult to treat with steroids.

A second major research project we have undertaken is to determine just how many long term resident immune cells are present in the lung and how they interact to cause asthma. Of particular interest is our finding that up to 10% of isolatable lung cells can be NK cells which have the potential to dampen down many of the symptoms of asthma. We have been studying whether key chemicals could be used to trigger these NK cells to suppress asthma. Discoveries from this asthma study may protect humans and livestock from parasitic diseases.