Medicine, University of Southampton

Stephen Holgate is Medical Research Council Clinical Professor of Immunopharmacology at the School of Medicine, Southampton, UK. After completing his medical training in London he spent 2 years at Harvard Medical School to acquire skills in allergic disease mechanisms. On returning to Southampton in 1980, he set up a research group focused on the mechanisms of asthma. He has utilized many approaches to study this disease including epidemiology, genetics, pathology, microbiology and immunology, pharmacology and experimental medicine. This research has informed guidelines on asthma management and has identified and validated novel therapeutic targets.

His work has resulted in over 920 peer reviewed publications (H index 106), 52 Book editorships, 450 Book Chapters and Reviews, 48 Editorials, 68 Official and Government Reports. He holds an MRC programme grant focused on the pathogenesis of asthma over the lifecourse.

He is a Past President of the British Society of Allergy and Clinical Immunology and British Thoracic Society. He is Chair of the MRC Population and Systems Medicine Board and Member of MRC Strategy Board and Chair of Panel A (covering Medicine, Health and Life Sciences) of the UK Research Excellence Framework 2014 (to assess research and impact in all UK Universities over the previous 5 years). He is Chair of the UK Government Advisory Committee on Hazardous Substances and Member of the Committee on the Medical Effects of Air Pollutants.

Qualifications

BSc Biochemistry (Class I), London University (1968)
MB BS, Medicine/Surgery, London University (Charing Cross Hospital Medical School) (1971)
MD, Asthma Research, London University (1979)
DSc, Inflammatory Basis of Asthma, University of Southampton (1991)

Postgraduate Fellowships

MRCP (UK), Royal College of Physicians (1973)
FRCP, Royal College of Physicians of London (1984)
FRCP (Edin), Royal College of Physicians of Edinburgh (1995)
FMedSci, Foundation Fellow, Academy of Medical Sciences (1997)
FSB, Biological Society, (1999)
FRCPath, Royal College of Pathologists, (1999)
FBMS, Institute of Biomedical Science, (2009)
CSci (Hon), Science Council, (2009)

Honours and Distinctions

1978 Medical Research Council Dorothy Temple Cross & Wellcome Trust Travel Fellowship
1990 Philip Ellman Lecturer, Royal College of Physicians
President, British Society of Allergy and Clinical Immunology (BSACI) (to 1993)
1991 Hurst Brown Visiting Professorship, University of Toronto, Canada
Altounyan Lecture, British Thoracic Society
1992 Cournand Lecture, European Respiratory Society
1993 James-Parkinson Memorial Lecture, Society of Occupational Medicine
Thomas Young Medal, St George's Hospital, London
Royal College of Physicians Graham Bull Prize for Clinical Research
1994 Lilly Lecture, Royal College of Physicians of Edinburgh
CIBA Foundation Lecture, Science Festival, Edinburgh
Jack Pepys Lecture, British Society for Allergy and Clinical Immunology
Scientific Achievement Award, International Association of Allergy and Clinical Immunology,
Stockholm
1995 Robert Cooke Memorial Lecture, American Academy of Allergy and Immunology
Visiting Professor, Ontario Thoracic Society, Canada
Rhône-Poulenc Rorer World Health Award ($20,000)
1996 Honorary Fellow, South African Pulmonology Society
Priscilla Piper Memorial Lecturer, Royal College of Surgeons
Honorary Member, Nordic Society of Allergology
Evening Discourse, Royal Institution of Great Britain
Visiting Professor, Vanderbilt University, USA
1997 Visiting Professor, Harvard University, Boston, USA
Doctorate Hon Causa, University of Ferrara, Italy
1998 Visiting Professor, University of Rochester USA
Brian Sproule Lecture, University of Alberta, Canada
Doctorate Hon Causa, Jallegonian University, Krakow, Poland
1999 King Faisal International Prize in Medicine (Gold Medal, $200,000 - shared with Patrick
Holt, Australia)
Medal for Scientific Achievement, Rijksuniversity, Gent, Belgium
Ranked No.8 in UK Citations in Biomolecular Subjects (ISI), 1990-2000
2000 Lumleian Lecture, Royal College of Physicians
Robert Cooke Memorial Lecture, American Academy of Allergy, Asthma and Immunology
Honorary Member, Germany Society for Pulmonology
Alec Sehon Distinguished Professorship in Allergy, University of Manitoba, Canada
2001 Visiting Professor, Yale University School of Medicine
The Honorary Fellow Award, American Academy of Allergy, Asthma & Immunology
Visiting Professor, Harvard Medical School, Boston, USA
Czech Republic Medical Society Medal for Scientific Achievement, Prague
Overseas Fellow, Polish Academy of Science
ISI Most Highly Cited Researcher for Publications 1980-2011
Visiting Professor, Thomas Jefferson Medical College, Philadelphia, USA
2002 Visiting Professor, University of Cincinnati Medical Center, USA
Norman Sterrie Lecture, University of Minnesota, USA
Highly Cited Researcher (Original Member, Highly Cited Researchers database, ISI)
2003 Sir William Osler Lecture, Association of Physicians of GB and Ireland
2004 Ellison-Cliffe Medal, Royal Society of Medicine
GB West Memorial Lecture, European Histamine Research Society
Scientific Achievement Award, International Association of Asthmology (Interasma)
2004 Visiting Professor, University of Michigan, Ann Arbor, USA
Visiting Professor, Wake Forest University, Winston-Salem, N Carolina, USA
Health and Life Sciences Gold Medal, Rijksuniversity, Gent, Belgium
Honorary Member, Association of Physicians of Great Britain and Ireland
Honorary Fellow, American College of Asthma, Allergy and Immunology (ACAAI)
Honorary Member, Biochemical Society
British Pharmacological Society Quintiles Prize in Immunopharmacology
Hospital Doctor Academic Medicine Team of the Year Award
2005 Overseas Member, American Association of Physicians (AAP)
Visiting Professor, University of British Columbia, Canada
Visiting Professor, UCSF and the Sandler Asthma Foundation, USA
Sir Anthony Dawson lecture, Royal London and St Bartholomew’s Hospitals
2006 The Huxley Lecture, Imperial College, London
Burns Lecture, RCP Glasgow
Honorary Member, DGAKI (German Society of Allergy and Clinical Immunology)
President of the British Thoracic Society
2007 Visiting Professor, John Hopkins Bloomberg School of Public Health, Baltimore, USA
Visiting Professor Harvard Medical School, Boston and Ohio State, University, Ohio, USA
BMA Medical Book of the Year Award for Allergy 3rd edition
Royal Society of Medicine Book Commendation for Allergy 3rd edition
2008 Paul Ehrlich Award for Research, European Academy of Allergy, Asthma and Clinical
Immunology
2009 Opening Plenary Lecture, Keystone Conference on Asthma and Allergy
Honorary Fellowship of the Institute of Biomedical Science
Council of the Academy of Medical Sciences
Honorary Chartered Scientist (CSci), Science Council
2010 David W Talmage Lectureship, Aspen Allergy Jack Selner Conference, Colorado
Jeffrey Drazen Visiting Professor, Harvard Medical School
2011 Commander of the Order of the British Empire (Queen’s New Year Honours List)
Honorary Life Membership of the Primary Care Respiratory Society UK,
2012 Miegunyah Distinguished Visiting Fellowship, University of Melbourne
American Thoracic Society Recognition Award for Scientific Accomplishments

Appointments held

House Physician, Charing Cross Hospital, London, 1971-2

Senior House Officer (Neurology), National Hospital for Nervous Diseases,
London, 1972-3

Senior House Officer (Respiratory Medicine & Cardiology), Brompton Hospital, London, 1973-4

Registrar (General Medicine), General Infirmary, Salisbury & Southampton General Hospital, 1974-5

Lecturer and Honorary Senior Registrar in Medicine, Southampton General and Western Hospitals, 1975-80

MRC and Wellcome Trust Overseas Research Fellow, Harvard University, Boston, USA, 1978-80

Lecturer in Medicine and Honorary Senior Registrar, University of Southampton Hospitals, 1975-80

Senior Lecturer, Reader then Professor of Medicine and Hon Consultant Physician, Southampton University Hospitals, 1980-6

MRC Clinical Professor of Medicine, Southampton University and Foundation Trust, 1987-present

Research is focused on the causes of asthma and its treatment

Allergens and asthma: Using a variety of epidemiological and experimental medicine approaches, over 30 years atopy and the level of allergen exposure were shown to be major factors in the origins and persistence of asthma through the generation of allergen-specific IgE which interacts with human airway mast cells to release a range of inflammatory mediators. This work continues looking at those early life factors that drive the origins of asthma including, maternal, epigenetic and early life exposures. This work is conducted collaboratively using longitudinal birth cohort studies as well as targeted in vitro composite cell test systems.

Subphenotyping asthma: Depending upon their location, mast cell subtypes were shown to drive aspects of chronic as well as acute asthma. I established that persistent asthma also involves chronic T lymphocyte-driven inflammation with the secondary recruitment of circulating leukocytes (especially eosinophils) in proportion to disease severity, suppression of which explained the beneficial effects of corticosteroids and other anti-inflammatory controller drugs. Severe asthma has been shown to comprise a spectrum of subtypes with differences in their inflammatory profile leading to variation in response to specific environmental, drug and biological interventions (stratified medicine). Current work is focused on further subphenotyping asthma through causal pathways using a range of molecular biomarker, physiological, pharmacological and genetic transcriptome and proteomic approaches.

Asthma excacerbations: A series of different experimental approaches have also established that most acute worsening of asthma (exacerbations) is caused by common respiratory viruses which infect the airway epithelium as a consequence of deficient primary anti-viral interferon production which is insensitive to corticosteroids. Based upon this we are close to completing a proof-of-concept trial of inhaled IFN-β1a for virus exacerbations in severe asthma. To compensate for defective local innate immunity, a comprehensive gene transcipional analysis of circulating momonuclear cells before, during and after acute exacerbations in a multinational study has revealed exacerbations invoke a powerful systemic innate (IFN-dominant) and weaker adaptive immune response. Our work is now focused on determining the way common respiratory viruses interact with dendritic cells to enhance early life allergen sensitization. In 2004, a university spin out company was formed that continues to investigate inhaled interferon-β as a new treatment for exacerbations in both asthma (adults and children) and COPD as well as new indications in pandemic influenza.

Airway remodelling: Both in asthmatic children and adults, increased airway epithelial susceptibility to injury and defective repair leads to persistent inflammation and airway wall remodelling.The existence of a unique epithelial phenotype in asthma characterised by reduced barrier function, exaggerated repair responses and altered gene networks governing allergic sensitisation, innate immunity and responses to injury has led to the concept of activation of the epithelium and underlying structural elements - the epithelial-mesenchymal trophic unit - being fundamental to the origins and progression of asthma. The epithelium in asthma is defective in response to injury and fails to form tight junctions leading to increased penetration by inhaled particles (pollutants), allergens and microorganisms to increase the asthmatic inflammatory responses. A key question that these studies identify is whether the epithelial set point for responding to environmental injury and aberrant repair is fundamentally altered. In collaboration with colleagues in Cincinnati, the transcription factor NKX2-1 (thyroid transcription factor 1) in airway epithelial cells of biopsies and brushings from patients with asthma is suppressed which, when replicated in the epithelium of heterozygous NKX2-1 in gene-targeted mice, increased mucous metaplasia, altered innate immunity and enhanced Th2-regulated inflammation all features of asthma, by influencing sentinel gene networks. Future work will focus on the role of such epithelial gene networks in driving abnormalities in this physical and functional barrier. In order to determine the pivotal role the abnormal asthmatic epithelium has in driving airway wall remodelling in vivo repeated bronchoconstriction in the absence of inflammation was sufficient to initiate remodelling with epithelial mucous metaplasia, growth factor release and mucosal collagen deposition that could all be effectively blocked by prior administration of a long acting inhaled β₂  -agonist bronchodilator. Thus, in addition to controlling airway inflammation, this study indicates that good asthma control also requires the use of bronchodilators as functional antagonists in order to reduce episodic bronchoconstriction to linked to structural airway remodelling and disease chronicity. Underlying mechanisms and its clinical significance is now being pursued.

Asthma genetics: In pursuing factors that contributed to remodeling of the airways driven through the EMTU in asthma, we used positional cloning to uncover the first novel asthma susceptibility gene, A Disintegrin Metalloprotease 33 (ADAM33) located on chromosome 20p13 encoding a multifunctional 120kD protein selectively expressed in airway fibroblasts and smooth muscle (17). Subsequently,polymorphism of ADAM33 was shown to be associated with reduced lung function in childhood, acquisition of AHR and an accelerated decline in lung function over time, all features of chronic asthma. The discovery of a soluble 55kD fragment of ADAM33 with enzyme properties capable of driving new blood vessel formation has provided one mechanism for airway remodelling. Further studies have revealed that several ADAM33 protein isoforms occur in adult bronchial smooth muscle and embryonic bronchi suggesting its importance in smooth muscle development/function, helping explain its genetic association with the inception of asthma and AHR. High but transient over-expression of ADAM33 in embryonic mesenchymal cells stem cells and tight epigenetic regulation supports its role in airway morphogenesis and the early life origins of asthma. Genetic studies have also identified PCDH1 and ATPAF1 as new candidate genes in the epithelium and smooth muscle. Focus will be on determining gene function and epigenetic regulation.

Translation of novel targets into treatments: Over a prolonged period identification of novel therapeutic targets in asthma has led to the study of new treatments. Severe chronic asthma accounts for ~50% of the health costs of this disease and is heterogeneous. A large EU project (ENFUMOSA) revealed aspirin intolerance as a contributory factor in over 25% of patients. This resulted from the release of high levels of cysteinyl leukotrienes generated from greatly enhanced mast cell and eosinophil LTC4 synthase activity. A clinical trial confirmed the high efficacy that leukotriene blockade has in this asthma subtype. A second type of severe asthma was associated with elevated serum total IgE. The safety and efficacy of blocking IgE in humans was shown using a chimeric mouse/human IgG monoclonal antibody directed to the IgE-high affinity receptor (Fcε) binding site on mast cells to prevent their activation. This novel approach to treatment has been highly successful in the form of a humanised IgG anti-IgE monoclonal antibody (omalizumab), which has been approved for use in treating severe allergic asthma in which conventional treatments have failed. Omalizumab not only depleted circulating and IgE in the airways, but also reduced the number of Fcε receptors present on the surface of mast cells thereby further reducing their capacity to release mediators. ENFUMOSA also uncovered a third asthma subtype characterised by lack of atopy, corticosteroid refractoriness and a prominent neutrophilic airway inflammation. In this form of the disease, the multifunctional cytokine TNFα proved to be an important driver of the inflammatory response and led to our first proof-of-concept trial of TNFα blockade using the soluble receptor fusion protein, etanercept. As new targets are uncovered novel therapeutics are studied in the National Institute for Health Research Respiratory Research Unit in Southampton.

Academic unit:  Clinical and Experimental Sciences