Pharmacological induction of allergen-specific IL-10 secreting regulatory T cells in allergy and asthma

Allergic and asthmatic disease is highly prevalent in the UK, causing great impairment in the quality of life and a massive burden on NHS resources. Current treatments such as steroids, although effective in many individuals, are largely palliative, that is they relieve the symptoms of disease, but do not cure or provide long-lasting relief. Allergen immunotherapy represents a treatment that can provide long-term alleviation of disease symptoms but is only effective in a proportion of patients, carries significant risk of adverse side effects and needs to be given over a prolonged period of time (several years) for maximal efficacy. Thus there is a clear unmet need for novel or improved treatments to control allergic and asthmatic disease.

Based on a large body of published work from Dr Hawrylowicz, Professor Corrigan and independent groups, we propose that there is added benefit in combining the well-tried and tested non-specific effects of drugs such as steroids with specific allergen immunotherapy to improve the safety, longevity and efficacy of treatment. We are proposing to test this concept in the laboratory with cells obtained from the peripheral blood and the nose that is the active site of disease, of allergic patients.

We propose that the pharmacological induction of IL-10-secreting T regulatory cells (IL-10-Treg) is a novel and potentially important therapeutic candidate for allergic disease. We previously demonstrated that activation of human CD4+ T cells in the presence of dexamethasone and 1 25dihydroxy vitamin D3 induces IL-10-Treg experimentally. We will now extend these studies and identify the cellular origins and optimal conditions for generation of allergen-specific IL-10-Treg using peripheral blood and respiratory tissue from allergic patients. Specifically the project will ask:

i. Which cytokines positively or negatively influence the development and function of IL-10-Treg?
ii. Can IL-10-Treg be derived from previously activated allergen-specific Th2 cells?
iii. Can IL-10-Treg be generated from nasal tissue, the active site of disease, from patients with allergic rhinitis and polyposis?

Our rationale is that drugs such as steroids and 1 25dihydroxy vitamin D3 could be used in combination with antigen-specific tolerance-inducing regimens like allergen immunotherapy, to enhance the generation of allergen-specific IL-10-Treg in patients and so improve the clinical efficacy and potentially also the safety of allergen immunotherapy. The overall aim of the present study is to provide experimental evidence to facilitate a future clinical trial in this area.

The proposed study will provide a comprehensive training in the immunology of allergic disease, both cellular and molecular, and insight into translational research in the field of allergy. This will be greatly facilitated under the training provided through the MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, which will increase both the breadth of knowledge and provide a forum to develop critical thought. This includes research expertise (theoretical and technical) in the areas of IgE regulation & structure, Th2 cytokine gene cluster regulation, airway inflammation & leukocyte trafficking, animal models of acute and chronic allergic airway disease, and immunomodulation (including allergen immunotherapy, regulatory T cells and dendritic cells). Experimentally the candidate will acquire a range of skills including cell isolation from blood and tissue, purification and culture, functional assays of regulatory T cell function, flow cytometric analysis and cell sorting, ELISA/multiplex analyses, and quantitative RT-PCR.