Asthma, Allergy & Lung Biology (AALB) (Research Division)

The research in the Hawrylowicz laboratory is aimed at understanding immunological mechanisms that ensure respiratory health, which requires the effective clearance of pathogens in the face of controlled and limited inflammation, and how these change in asthmatic disease. Defining the role of vitamin D in maintaining respiratory health is a major focus. This includes the study of the capacity of vitamin D to enhance regulatory T cell populations and anti-inflammatory pathways, and its effects on innate and structural cells lining the airways. These translational studies involve investigation of peripheral cells and respiratory tissue from paediatric and adult asthma patients, as well as studies of neonatal peripheral blood cells. Her group is involved in clinical trials of treatment with vitamin D in severe steroid refractory asthma and of vitamin D supplementation in pregnancy in order to evaluate the capacity of vitamin D to treat and prevent disease.

Gould, with Fear and Corrigan have discovered that somatic hypermutation, class switching and IgE protein synthesis occur in the nose in allergic rhinitis and airways of both atopic and non-atopic asthmatics, suggesting that anti-IgE strategies may be beneficial in both groups of patients. Gould discovered that VH5 is over-represented in the nasal allergenic IgE response suggesting that a superantigen, such as the S. aureus enterotoxins, may play a role in the pathogenesis of allergic disease. Together with Beavil, they are also cloning and expressing whole IgE antibodies, as well as the corresponding scFv fragments, specific for grass pollen allergens and S. aureus superantigens for functional analysis of the IgE molecules, and crystal structure determination of the Fv-allergen/superantigen complexes by Sutton. An MRC Programme grant was awarded to Sutton, Gould and Beavil in 2006 to support this research, which has been renewed in 2011 to include additional collaborations with McDonnell and Lack to study the IgE and IgG4 response to peanut allergens.

Gould and Fear have investigated the transcriptional and chromatin landscape of the entire immunoglobulin heavy chain locus and the IgE gene (at high resolution) during the process of class switching to IgE. They have also studied the mechanism of DNA recombination events associated with class-switching, using ultra-high resolution microscopy. Together these studies have disproved a long held dogma that IL-4 stimulates switching to IgE in B cells by causing local unfolding of chromatin structure in the region of the IgE epsilon heavy-chain gene and have identified key histone modifications that may regulate the recombination process. In addition, Fear has been using transcriptomic and epigenetic analyses to identify the transcription factors, chromatin remodelling enzymes and microRNAs that regulate the process of class switching to IgE. Fear has also been studying the mechanisms regulating the activity of the enzyme Activation Induced Cytidine Deaminase (AID) in human B cells by Chromatin Immunoprecipitation and “next-generation” sequencing technology. AID plays a central role in the initiation of the immunoglobulin diversification events that take place in mature B cells, somatic hypermutation and Class switching, and plays a role in B cell lymphomagenesis. These studies have identified the mechanisms that may recruit AID to the immunoglobulin locus and shed light on where this process breaks down in lymphomagenesis.

Cousins and Lavender have been studying the mechanism of T cell differentiation using both transcriptomic and epigenetic analysis. This work has revealed the identity of a number of cell-type specific transcripts and shown that this differential gene expression is facilitated by establishment of cell type specific chromatin environments and expression of non-coding RNA transcripts that are likely to be involved in maintaining transcriptional competence of loci during lineage commitment. They are continuing to study the chromatin organisation and DNA methylation states of human Th1 and Th2 cells to gain a deeper understanding of the mechanisms of Th2 cell lineage commitment and IL-4, IL-5 and IL-13 gene expression. With Susan John, Lavender and Cousins have demonstrated a role for STAT5 in transcriptional regulation of the transcription factor c-Maf and shown regulation of expression of this factor by the IL-2 pathway.

Cousins, Fear, Lavender and Woszczek are studying transcriptome and epigenome landscapes, miRNA biology and signalling processes of specific cell types that may contribute to the development of asthma. These include T helper lineages, B cells, Airway Smooth Muscle and Bronchial Epithelial cells. We study these processes during lineage specification, differentiation and activation.

Research in the Cousins laboratory focuses on human CD4-positive T-helper cell lineage commitment, with a particular interest in Th2 cell differentiation and function. We have been using microarray platforms for a number of years to identify novel Th2 specific genes and microRNAs. Our current studies are aimed at examining the function of several novel transcription factors and miRNAs in Th2 cell development using in vitro differentiation and lentiviral transduction to overexpress or ‘knock-down’ the gene of interest. In collaboration with the Lavender laboratory we also study the epigenetics of human T-helper cells using ChIP-sequencing and DNA methylation analyses.

Gould and Fear are investigating the transcriptional and chromatin landscape of the entire immunoglobulin heavy chain locus and the IgE gene (at high resolution) during the process of class switching to IgE. They also study the mechanism of DNA recombination events associated with class-switching, using ultra-high resolution microscopy. Together these studies have disproved a long held dogma that IL-4 stimulates switching in B cells by causing local unfolding of chromatin structure in the region of the Ig heavy-chain gene and have identified key histone modifications that may regulate the recombination process. In addition, Fear is using transcriptomic and epigenetic analyses to identify the transcription factors, chromatin remodelling enzymes and microRNAs that regulate the process of class switching. Fear also studies the mechanisms regulating the activity of the enzyme Activation Induced Cytidine Deaminase (AID) in human B cells by Chromatin Immunoprecipitation and “next-generation” sequencing technology. AID plays a central role in the initiation of the immunoglobulin diversification events that take place in mature B cells, somatic hypermutation and Class switching, and plays a role in B cell lymphomagenesis. These studies have identified the mechanisms that may recruit AID to the immunoglobulin locus and shed light on where this process breaks down in lymphomagenesis.

Lavender and colleagues investigate chromatin landscapes and their influence over gene expression potential. They have undertaken genome-wide analysis of location of specific post-translationally modified histones that indicate expression potential and denote the localization of distal transcriptional regulatory elements in airway smooth muscle and T cell subtypes. They are currently mapping transcription factor binding onto these architectural landscapes. With Adcock and colleagues they have studied DNA looping at the 5q cytokine locus showing that the IL4 and 13 loci become juxtaposed to enable coordinate regulation.

Woszczek and colleagues’ research centres around molecular biology and signalling of G-protein coupled receptors (GPCRs) for lipid mediators such as leukotrienes, prostaglandins and sphingolipids and their role in inflammatory processes leading to acute and chronic changes in pulmonary diseases, i.e. bronchial asthma, COPD and pulmonary fibrosis. They have characterised leukotriene receptors expression, signalling and functions in human monocytes, endothelial cells, dendritic cells and Th2 cells. They are examining functions of receptors for leukotrienes and sphingolipids in human mast cells and airway smooth muscle cells from healthy and asthmatic subjects and their role in airway inflammation and remodelling. In addition, a potential role of orphan (non-characterised) GPCRs or new receptor variants in asthma and other respiratory diseases will be studied.

Additionally we seek to decipher the link between inflammation and carcinogenesis and mechanistically how the tumour microenvironment supports cancer propagation. We focus on novel culprit molecules and pathways involving growth factors, integrin signalling and immunomodulation in the context of lung cancer and chronic respiratory conditions such as idiopathic pulmonary fibrosis. Our aim is to identify how these molecules interact with the inflammatory microenvironment using in vitro and in vivo models, and to translate this to potential new therapies for pulmonary fibrosis and lung cancer.

The paediatric respiratory physiology research group at King’s College London focuses on prevention of chronic respiratory morbidity following premature birth, optimising neonatal and paediatric respiratory support, promoting antenatal lung growth and reducing the effect of chronic disorders on the respiratory function of children. The group is lead by Professor Anne Greenough, who is an NIHR Senior Clinical Investigator and Chair of the NIHR Paediatrics Specialty Group.

The Lung Biology group uses physiological measurements to test hypotheses, develop new techniques and assess the efficacy of interventions in fetal, neonatal and paediatric respiratory medicine. The research group is in the KCL Division of Asthma, Allergy and Lung Biology and AG is a PI in the Medical Research Council/Asthma UK Centre for the Allergic Mechanisms of Asthma. The research is in four main areas:

1. Neonatal and paediatric ventilation
Physiological techniques have been used to optimise the delivery of high frequency oscillatory ventilation (HFOV) and then supported by the MRC a multicentre trial (UKOS) was undertaken. Currently supported by the NIHR HTA programme (portfolio study), AG is comprehensively assessing the UKOS children now aged 11-13 to determine whether HFOV is protective of small airway function without adverse effects on pulmonary hypertension or neurodevelopmental outcomes. The group, supported by the Charles Wolfeson Charitable Trust, is also currently investigating how the newer modes of mechanical ventilation, including volume limited, pressure support and proportional assist ventilation, can be used to provide optimal respiratory support for prematurely born and term born infants. With colleagues from the University of Rotterdam, Professor Greenough is undertaking a randomised trial to determine the optimum method of ventilating infants with congenital diaphragmatic hernia, in particular we have designed the follow-up assessments.

2. Prevention of chronic respiratory morbidity following premature birth
Follow-up studies to quantify respiratory morbidity following very premature birth have been undertaken; the long term respiratory assessments developed are now being used, rather than bronchopulmonary dysplasia (BPD), as outcomes in multicentre trials. Biomarkers for the development of BPD and long term adverse respiratory outcomes are being investigated, current support is from the NIH. AG has demonstrated that Respiratory Syncytial Virus (RSV) infection in the first two years after birth increases chronic respiratory morbidity and lung function abnormalities even at school age in prematurely born children. Those data influenced changes in the UK Joint Committee of Vaccines and Immunisations’ guidelines regarding RSV prophylaxis. Currently, supported by the BRC and Abbott, the importance of premorbid lung function and genetic polymorphisms in determining outcome in prematurely born infants who develop RSV infection is being assessed in collaboration with Prof Bont, University of Utrecht. Prematurely born infants are at increased risk of sudden infant death syndrome (SIDS). Supported by the Foundation for the Study of Sudden Infant Deaths, the effect of posture on respiratory control and function has been examined and national evidence-based guidelines for sleeping position of prematurely born infants after NICU discharge produced. Currently, supported by KCH R and D and led by Dr Bhat, the group is investigating the interaction of maternal substance abuse on respiratory control in prematurely born infants, particularly at the high risk age for SIDS. We are also currently, supported by the GSST charity, undertaking studies to optimise neonatal resuscitation and supported by the KCH and GSST charities, undertaking research to improve breast feeding rates and parent experience on the neonatal unit.

3. Antenatal lung growth
Impaired antenatal lung growth is a common outcome, pulmonary hypoplasia being found at 10% of neonatal postmortems. In collaboration with Professor Nicolaides, the accuracy of antenatal diagnostic tests are being assessed by relating the results to infant respiratory outcomes. With Professors Moxham and Davenport and led by Dr Rafferty, the role of diaphragmatic function in abnormal lung growth, particularly in infants with surgically correctable lung anomalies, is being investigated. This has involved the development of novel tests of diaphragmatic and small airway function in neonates.

4. Effect of chronic disorders on respiratory function in children
Vital to diagnosis and appropriate treatment of respiratory morbidity is quantification of any abnormality. An important area of research has been the development of appropriate lung function tests for all ages, even those receiving intensive care. Supported by the Medical Research Council and the Community Fund, two cohorts of children and adults with sickle cell disease (SCD) in South London with Prof Thein, Drs Height and Rees and in Jamaica with Dr Knight- Madden are being followed. The prevalence of lung function abnormalities in those populations has been determined and ethnically appropriate reference ranges established. A significant association of asthma and the pulmonary complications of SCD, acute chest syndrome and sickle chronic lung disease, has been demonstrated. Currently the impact of asthma/reactive airway disease and the acute chest syndrome on the speed of decline in lung function in SCD patients is being investigated. In addition, the utility of CT scan assessments of respiratory status and pulmonary hypertension are being investigated with Prof Shah and Dr Desai.

Lack demonstrated that cutaneous exposure to peanut allergen is a risk factor for developing peanut allergy. This has resulted in a number of manufacturers removing peanut and other nut oils from their topical products. Early oral exposure to peanut is associated with the development of tolerance to peanut, raising the possibility that current guidelines that promote peanut avoidance during the first three years of life may actually promote development of peanut and nut allergies.

Greenough demonstrated that RSV and other viral infections increase the risk of chronic respiratory morbidity/asthma in infants born prematurely. This resulted in changes in the recommendations by the Joint Committee of Vaccines and Immunisations regarding RSV prophylaxis. She also showed that the majority of very prematurely born infants develop bronchopulmonary dysplasia (BPD), require frequent hospital admissions and anti-asthma medication.

She has developed novel techniques of neonatal respiratory support. This research has been central to a Cochrane review and national and international evidence based guidelines. Her critical assessment of the respiratory outcome of infants and children has informed changes in practice regarding antenatal diagnostic and therapeutic interventions. The Foundation for Sudden Infant Death Syndrome has used her research to inform their recommendations for the safe sleeping position for prematurely born infants with the hope of reducing sudden infant death in this high risk population. She has shown that in children with sickle cell syndrome (SCD) both in Jamaica and the UK asthma may predispose to episodes sickle cell crises and that asthma leads to recurrent crises, important causes of mortality and morbidity in SCD patients.

Moxham was the first to demonstrate that non-invasive ventilation (NIV) was helpful in acute exacerbations of COPD. NIV is now standard practice in the management of acute exacerbations in COPD. He also demonstrated that pulmonary rehabilitation immediately following an exacerbation of COPD improves quality of life, increases exercise capacity and reduces use of healthcare resources. Ventilatory load is reflected by central respiratory drive, which can be accurately recorded in terms of the diaphragm EMG using a new multielectrode catheter which he invented. He demonstrated that muscular weakness in COPD is likely to be due to inactivity rather than a systemic inflammatory process as suggested by others. Patients with severe obstructive airways diseases may have secondary pulmonary hypertension. Ward and Aaronson demonstrated that the oxygen sensor linked to the elevation of calcium during hypoxic pulmonary vasoconstriction (HPV) involves complex III of the mitochondrial electron transport chain and is due to an increased reactive O2 species. They also defined the role of the endothelium as a critical component of sustained HPV, mediated via potentiation of Rho kinase mediated calcium sensitisation. These findings suggest new opportunities for intervention to reduce morbidity.

Lack is conducting a 7-year NIH-funded interventional study (LEAP) to induce oral tolerance to peanuts by feeding peanut proteins to atopic infants. He is also PI on a 5 year MRC/FSA funded interventional study (EAT) comparing exclusive breast feeding for 6 months with the early introduction of allergenic solids. If the approach is successful it may introduce a completely new paradigm for the prevention of food allergy and will have important implications for public health policy on infant nutrition worldwide.

These studies will use unique physiological techniques that Greenough and Rafferty have developed to assess lung function and bronchial hyperresponsiveness in children. Greenough and Rafferty will identify whether prematurely born infants with premorbid lung function abnormalities or with certain genetic predispositions are at increased risk of developing severe RSV disease and subsequent asthma and hence inform criteria for administering prophylactic therapies. Greenough will follow up her unique large cohort of very prematurely born children and determine whether at school age respiratory outcome has been influenced by neonatal ventilation mode. She will determine whether anti-asthma medication reduces the devastating pulmonary morbidity of SCD patients.

Ward and Aaronson will ascertain the molecular identity, expression, and signalling pathways of channels underlying Ca2+ entry and protein kinases regulating Ca2+ sensitivity and thus contraction of pulmonary artery and human airway smooth muscle and small bronchioles. A key goal is to characterise the functional consequences of changes in expression and/or function of these pathways that are associated with asthma and chronic hypoxic lung diseases, thereby providing insight on new targets for therapeutic intervention.

Moxham will extend his studies of early pulmonary rehabilitation in patients with COPD exacerbations including analysis of quadriceps biopsies in collaboration with Prof Herridge. Recent work suggests overlap in mechanisms of COPD and severe asthma. As Moxham is already developing better measures of disease outcomes in COPD, we are poised to test them in severe asthma.

The group is focussed on the physiology and pharmacology of chronic respiratory disease, including asthma, COPD and sleep apnoea, and the effects of hypoxia and oxidant stress.

Ward and colleagues are studying calcium homeostasis in human airway smooth muscle cells from asthmatics to define the molecular basis of the abnormal airway smooth muscle phenotype in asthma. They have discovered that the expression of a key protein (SERCA2) is reduced in asthmatic airway smooth muscle, and that expression of other proteins associated with calcium is affected by inflammatory mediators and oxidative stress. Together, these changes may underlie the modified phenotype and smooth muscle hyperresponsiveness in asthma. They will be analysing both the causes and consequences of such changes and the influence of key therapies, particularly in terms of airway remodelling in severe asthma.

In parallel with the above, Knock and Ward are also investigating the Ca2+-independent regulation of airway smooth muscle function, particularly in relation to the RhoA/Rho-kinase pathway. They are currently focussing on the modulation of this pathway by non-receptor tyrosine kinases Src and focal adhesion kinase and how this may be altered in asthma and in response to inflammatory cytokines.

Woszczek and colleagues’ research has centred around molecular biology and signalling of G-protein coupled receptors (GPCRs) for lipid mediators such as leukotrienes, prostaglandins and sphingolipids and their role in inflammatory processes leading to acute and chronic changes in pulmonary diseases, i.e. bronchial asthma, COPD and pulmonary fibrosis. They have characterised leukotriene receptors expression, signalling and functions in human monocytes, endothelial cells, dendritic cells and Th2 cells. They will be examining functions of receptors for leukotrienes and sphingolipids in human mast cells and airway smooth muscle cells from healthy and asthmatic subjects and their role in airway inflammation and remodelling. In addition, a potential role of orphan (non-characterised) GPCRs or new receptor variants in asthma and other respiratory diseases will be studied.

Aaronson, Knock and Ward have an on-going study into the mechanisms regulating pulmonary vascular tone in hypoxia, and have shown that oxidant signalling is critical for both the hypoxia-induced calcium elevation and Rho kinase activation in pulmonary artery smooth muscle, and may involve members of the src-kinases family. Membrane associated oxidant signalling induced by agonists such as sphingolipids may also facilitate or potentiate calcium entry mechanisms in pulmonary and system arteries, which may underlie vascular hyperresponsiveness in some forms of chronic or inflammatory disease.

Sleep apnoea is a very common condition, which is associated with increased risk of cardiovascular disease and type 2 diabetes. It has been strongly associated with increased oxidant stress as a result of intermittent hypoxia. The large cohort of patients with sleep disordered breathing, coupled with the cellular expertise available within the group, will facilitate studies on the causes and consequences of this condition and possible remedial therapies and novel management regimens, led by Hart and Ward.

Other studies include investigations on muscle weakness in COPD and aging patients and mechanisms to reverse this process (Rafferty, Hart, Moxham and Harridge).

Lavender and Professor Tak Lee (former Head of Division) discovered a new mechanism for GR repressive activity by GR binding to NFAT/AP1 sites and then recruiting co-repressor complexes that suppress GATA3 mediated activation. Corrigan and Sun have continued their investigation into the role of new remodelling mediators in the asthmatic bronchial mucosa, identifying the resistin RELM-b as a human airways remodelling mediator. Since other members of the resistin family regulate obesity and carbohydrate metabolism this provides a possible mechanistic link between obesity and asthma. They are collaborating with Dr Haczku (Pennsylvania) to study remodelling changes in a RELM-b gene deleted mouse, and also Drs Sehmi and O’Byrne (McMaster, Canada) to study influx of endothelial progenitor cells into the human asthmatic airways following allergen challenge. They have also furthered studies on the role of IL-25, showing that in addition to promoting Th2 T cell differentiation and memory it has the potential to exert a range of remodelling changes on a variety of target cells, including endothelial cells, smooth muscle and fibroblasts within the asthmatic bronchial mucosa. For example, they have shown that IL-25 acts on vascular endothelial cells to promote angiogenesis by inducing secondary VEGF production, a process which is dependent on PI3 kinase and MEK/ERK kinase signalling, highlighting these molecules as potential molecular targets for altering the natural history of airways remodelling in asthma. They have also shown that local mucosal expression of IL-25 is increased following environmental stimuli such as allergen exposure.. Through collaboration with Dr Wei Wang (Beijing) using a murine model they are investigating the potential for IL-25 to cause remodelling changes per se in the airways and the capacity of inhibitors of downstream targets induced by IL-25 such as PI3K isotypes to inhibit airways remodelling in vivo. Hawrylowicz has shown that glucocorticoids (GCs) fail to induce IL-10-synthesising human T regulatory cells in pediatric and adult GC resistant patients, which can be overcome by Vitamin D3. This exciting work has been extended into a clinical study to investigate whether Vitamin D3 supplementation increases the clinical response of severe asthmatics to systemic glucocorticoid therapy. This may uncover further novel therapeutic strategies for the treatment and prevention of asthma and other respiratory conditions, and this work is studying the effects of vitamin D in neonatal, pediatric and adult cell populations . Santis' studies suggest a critical role for alpha v beta 1 integrin in epithelial binding and internalisation of Adenovirus 5. Based on the structure of one of the adenovirus capsid proteins, he has designed novel constructs for cell type specific adenovirus targeting. Noble defined a distinct subset of CD8 regulatory T cells which prevent primary T cell responses to inhaled allergen.

Further work will investigate how regulatory T cell responses can be induced at the lung mucosal surface through novel immunotherapeutic approaches including the use of a potent MHC Class I-restricted peptide vaccine which inhibits Th2-mediated allergic lung inflammation. Corrigan's preseasonal immunotherapy trials have informed clinical management, resulting in the establishment of an ultra-short, preseasonal regimen for the treatment of allergic rhinoconjunctivitis. This has been incorporated into national immunotherapy guidelines (to which Corrigan contributed).. Lack has found that immunotherapy to grass pollen reduced symptoms and medication in children with allergic asthma by 50 per cent. His studies will form the basis for an MHRA application for a license to treat children with immunotherapy to grass pollen.

Corrigan and Sun will continue to elucidate mechanisms for refractory asthma phenotypes including glucocorticoid resistant and aspirin sensitive respiratory disease as well as severe, non-atopic asthma. A recent study on aspirin exacerbated asthma has confirmed and extended findings in the nasal mucosa in aspirin sensitive rhinosinusitis showing deficient expression of the prostaglandin E2 receptor EP-2 on bronchial mucosal leukocytes in the mucosa. Alongside this it was demonstrated that, of the four PGE2 receptors only EP-2 mediates inhibition of T cells, underlining the functional importance of this finding and highlighting EP-2 agonists, which have already been developed and suitable for possible therapeutic use, as promising therapeutic agents for the treatment of aspirin sensitive asthma. A novel ex vivo model using cultured nasal polyps from patients with aspirin sensitive rhinosinusitis continues to yield intriguing data and has the advantage of accounting for collaboration of the entire mucosal inflammatory cellular population in regulating the formation of eicosanoids in the airways, rather than looking at production by isolated populations of cells. This is important since a significant proportion of eicosanoid metabolism takes place extracellularly. A proof of principle study of the clinical effects of the humanised, monoclonal anti-IgE antibody omalizumab in non-atopic asthmatics continues: new techniques have been developed in collaboration with the pharmaceutical industry to detect local production of IgE in the bronchial mucosa of these patients not only to conventional allergens but also to putative “neoallergens” such as Staphylococcal enterotoxins. Hawrylowicz's group, while testing whether vitamin D3 has steroid sparing effects clinically, will continue analysis of the biochemical and immunological mechanisms which underpin these effects and identification of surrogate biomarkers of steroid responsiveness in severe asthma. She continues to investigate mechanisms by which vitamin D acts to promote healthy airways, by enhancing a number of anti-inflammatory pathways, and maintaining anti microbial pathways that allow effective clearance of pathogens in the face of controlled and limited inflammation. Santis will exploit the increased availability of active alpha v beta 1 integrin in airway inflammation to explore the use of different Ad serotypes to transduce antigen-presenting cells to shift Th2 towards regulatory T cell phenotypes. Corrigan will continue to utilise the clinical research facilities of the NIHR BRC Clinical Research Facility to collaborate with colleagues nationwide, such as through the ongoing application for an MRC funded Stratified Medicine Consortium project on asthma phenotyping, the government’s Translational Research Project initiative and Pharma (such as with our in house Phase I/II trials unit, Quintiles) to progress asthma phenotyping and investigate novel biological agents as they become available.

Alistair Noble’s group is investigating regulatory pathways in the immune system that might explain how a westernised lifestyle with low levels of infection could have resulted in the increased incidence of asthma and allergic disease. His research is focussed on the development of T cell subsets, which are central in regulating the immune system’s response to allergens in asthma. He recently established a role for Th17-type T cell responses in airway remodelling in experimental asthma, and aims to improve understanding of T cell subset regulation in acute and chronic lung inflammation. The group is developing new experimental vaccines for immunotherapy of allergy and asthma without the need for continuous drug treatment, or for prevention of respiratory infections.

Till’s group is evaluating novel immunotherapy strategies for grass pollen-induced allergic disease. In particular he is currently conducting a clinical study funded by the MRC-NIHR Efficacy and Mechanism Evaluation Programme. This study encompasses a Phase II clinical trial and immunological assays and investigates an entirely novel approach to immunodulation involving low dose intradermal allergen injections to treat grass pollen-induced allergic rhinitis.