Asthma & Allergic Diseases Current Research

Project One: Modelling Allergy and the Th2 Immune Response

Conventional treatments for allergy and asthma, such as steroids, target the downstream steps of allergic inflammation. However, how the Th2 responses are induced in allergy and why some allergens preferentially promote Th2 responses in only a subset of individuals are still unknown.

To address these questions we have developed a novel assay to look at the early events of Th2 sensitisation in response to allergens known to trigger asthma such as house dust mites, pet dander, cockroaches and nematode worms. We are also working with Prof Richard Beasley to look at the effect of paracetamol on the induction of Th2 immune responses in our allergy model.

In 2008 Dr Elizabeth Forbes received funding to develop an experimental model that is relevant to human exposure through the skin, with a focus on the interrelationship of food allergy with other allergic disease processes. Previous studies have demonstrated that childhood allergic diseases often start in the skin as atopic dermatitis and later progress to the gastrointestinal and respiratory tracts.

The outcome of this research will be the development of scientifically sophisticated and physiologically relevant experimental models of allergy.

Project Two: The Basic Biology of the Th2 Immune Response

Before we can realistically start to provide practical advice on how best to avoid asthma and allergy, a greater knowledge of the basic biology of the Th2 immune response is required. Research published by our group in 2008, clearly illustrated that in vivo differentiation of naïve CD4 T cells to Th2 status can occur independently of IL-4 and STAT6 signaling; highlighting an as yet undefined alternative pathway for Th2 differentiation. Our current studies are focused on identifying alternative cytokine candidates and their potential roles in driving an IL-4-independent differentiation of Th2-mediated immunity to allergens and parasitic infection. We are also investigating the key parameters of Th2 protective immunity and the role of lymphocyte recirculation in allergic responses using the drug FTY-720.

Project Three: Parasites and the Th2 Immune 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. This information will assist in the development of vaccination strategies against these parasites.

Project Four: What Makes an Allergen, an Allergen?

We are using a multi-disciplinary approach to tackle the intriguing question of what makes an allergen, an allergen. Although much is known about the types of allergens that cause asthma, our knowledge of their molecular structures is very limited.

To define an allergen at the protein level we are extracting natural allergens and developing methods for their isolation and identification such as high performance liquid chromatography (HPLC), 2-Dimensional Gel Electrophoresis and MALDI Mass Spectrometry. These allergenic structures will be validated in our models of Th2 induction.

We are also testing a library of carbohydrate structures synthesised by the Malaghan Institute Immunoglycomics Group in our Th2 immune response assays. These structures were shown to be conserved on allergens such as pollen, food and worms but not present on antigens derived from bacteria and viruses that do not stimulate Th2 immune responses.

These studies will provide the first detailed insight into what makes an allergen at the protein and sugar levels, and will allow us to identify putative therapeutic targets for the treatment of allergic diseases.

Collaborators

Dr Volker Brinkman, Novartis CH

Dr Melanie Kleinschek, SP Biopharma, USA

Prof Rick Maizels, University of Edinburgh, UK

Dr Booki Min, Cleveland Clinic, USA

Dr William Paul, NIAID, National Institutes of Health, Washington DC, USA

Prof Neil Pearce & Assoc Prof Jeroen Douwes, Centre for Public Health Research, Massey University, Wellington, New Zealand

Prof Murray Selkirk, Imperial College London, UK

Funding Sources

AMI Insurance

Foundation for Research, Science & Technology (FRST)

Health Research Council of New Zealand

Marjorie Barclay Trust

New Zealand Lottery Health Research

Rex & Betty Coker Scholarship

The Royal Society of New Zealand Marsden Fund