Research Overview

Pavord Group

Background and Aims

Improved diagnostics for airway disease managed in primary care. Important outcomes such as hospitalisation and deaths from airway diseases such as asthma and COPD have not improved over the last 10 years despite a three-fold increase in expenditure on our most effective treatment (inhaled corticosteroids) to £470 million/year and considerable investment in initiatives to encourage adherence to treatment and better self-management. In the absence of any fundamental advances in treatments there are only two ways to address this lack of progress: to continue to persuade more patients to take more inhaled corticosteroids; or to target treatment more effectively. We are investigating the second approach. We will investigate the use of two simple biomarkers to inform decisions about the use of inhaled corticosteroids to prevent attacks and oral corticosteroid to treat attacks. Our focus will be on primary and emergency care where most important treatment decisions are made in patients with airway disease. We have shown previously in secondary care based studies that exhaled nitric oxide (FeNO) and the peripheral blood eosinophil count show considerable promise. The former is ideal for use in a non-specialist setting as the test is easy to perform and accurate results are assured. The latter is readily available in an emergency setting and shows considerable promise as a means of directing therapy in patients with COPD. We hope to develop a new approach to applying existing treatments where therapy is initiated based on the likelihood of a response. This approach has already been shown to be important for the use of new treatments in severe airway disease (see below).

New treatments for severe airway disease. Progress has been made in the development of new treatments for severe airway disease. We have played a lead role in the development of three of the most promising: Mepolizumab, bronchial thermoplasty and CRTH2 antagonists. An important insight has been to recognise that these treatments only work in sub-groups of patients who have evidence of activity of the relevant pathway. We believe that the only rationale approach to new drug discovery is to identify sub-groups of patients who share common characteristics, understand the key mechanisms of their disease and identify opportunities to intervene. We will do this in patients with severe eosinophilic airway disease, patients with airway disease associated with allergy to aspergillus and patients with persistent airway infection with Haemophilus Influenzae. We have chosen these sub-groups as they are common patterns of severe airway disease, existing treatments have some efficacy and the mechanisms of disease look tractable.

Bafadhel Group

Background and Aims

I work in the Department of Respiratory Medicine within the Nuffield Department of Medicine as a Senior Clinical Researcher in the field of Airways Disease, particularly chronic obstructive pulmonary disease (COPD). My research interests are investigating the mechanisms and therapeutic strategies aligned to using phenotypes of COPD and in particular during exacerbations. Broadly there are two inflammatory phenotypes of COPD that are identified by measurements of inflammation in the airway; eosinophilic and neutrophilic. These phenotypes are clinically indistinguishable but have different treatment responses. Initially working with sputum we have identified that during exacerbations of COPD approximately 30% have eosinophilic inflammation. I have identified that the peripheral blood eosinophil count is an excellent surrogate of eosinophilic airway inflammation in COPD and can identify sub-groups of patients that respond to corticosteroid therapy and those patients that have increased harm. The majority of COPD patients with neutrophilic inflammation were found to have increased detection levels of bacteria namely H. influenzae. These phenotypes have different treatment responsive disease, but little is known about the basic mechanisms of these COPD disease phenotypes, despite clinical similarities.

My ongoing research focus will be to develop a further understanding of the immuno-pathophysiology of COPD as determined by these identified clinical phenotypes, in addition to  delivering therapeutic strategies to patients working across the translational spectrum of this important airway disease; both in primary and secondary care. As part of my fellowship, I will seek to characterise patients with milder COPD disease and utilise near-patient point of care testing to provide improved stratified medicine personalised care with an aim of the right patient receiving the right treatment at the right time.

Xue Group

Background and Aims

The main aim of our research is to understand the molecular and cellular mechanisms mediating inflammatory diseases and to translate our findings into therapeutic concepts to treat these diseases. The current projects are:

The functions and signalling mechanisms of eicosanoids and their receptors
Both prostaglandin D2 (PGD2) and cysteinyl leukotrienes (LTs) have been detected in high concentrations at sites of allergic inflammation. Through its action on its receptor CRTH2, PGD2 elicits many pro-inflammatory responses in leukocytes. Pharmacological inhibition of CRTH2 represents a promising new treatment for allergic diseases. The leukotriene antagonists, most notably montelukast, have been approved for clinical use in asthma, and are effective inhibiting the CysLT1 (one of the receptors for LTs)-mediated bronchoconstriction but their anti-inflammatory activity is modest.

Our recent studies demonstrated that LTs, especially LTE4, greatly enhanced the inflammatory responses of human Th2 cells to PGD2. This synergistic effect was inhibited by montelukast. Combination of a CRTH2 antagonist and montelukast was required to completely inhibit the responses induced by the combination of PGD2 and LTs. The aim of the project is to understand comprehensively the functions and mechanism of these mediators in the pathogenesis of mast cell-mediated allergic inflammation and to provide the rationale for clinical use of antagonists targeting CRTH2 and leukotriene receptors, and finally lead to novel therapeutic strategy for the treatment of asthma.

The role of group 2 innate lymphoid cells (ILC2) in allergic asthma
Activation of ILC2 population leads to production of the classical type 2 cytokines, thus promoting type 2 immunity. Increased numbers of ILC2 have been detected in the inflamed nasal polyps and skin. In animal models the development of airway eosinophilia and airway hyperresponsiveness has been shown to be dependent on ILC2. We have also demonstrated the important role of PGD2 and its receptor CRTH2 in bridging innate and adaptive pathways in ILC2 cells. In this project, we would like to investigate 1) the profile of ILC2 in different sub-group of asthmatic patients including eosinophilic and neutrophilic severe asthma; 2) the potential role of ILC2 the pathogenesis of these patients; 3) the biology of ILC2.

Mechanism of RORγt and drug development for IL-17 mediated inflammatory diseases
Nuclear hormone receptor RORγt plays important role in physiological and pathological processes. RORγt+Th17 cells represent 30% of infiltrating T cells in some inflammatory diseases such as psoriasis. Small molecule inhibitors of RORγt inhibit the differentiation of human Th17 cells in vitro and reduce Th17 cell numbers and disease activity in animal models.  Comprehensive understanding of the role and mechanism of the activation of RORγt in RORγt positive cells will be a critical step prior to utilization of RORγt as a therapeutic approach for the treatment of ROR-mediated disorders. The aims of our project are: