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Medicine

Professor Stephen Holgate CBE, BSc, MB BS, MD, DSc, FRCP, FRCP (Edin), FRCPath, FIBMS, FSB, CSc (Hon), FMedSci

Medical Research Council Clinical Professor of Immunopharmacology and Honorary Consultant Physician, Honorary Visiting Research Professorship, University of Melbourne, Australia,Honorary Visiting Professorship in Translational Medicine, University of Manchester

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Professor Stephen Holgate is Medical Research Council Clinical Professor of Immunopharmacology and Honorary Consultant Physician within Medicine at the University of Southampton.

Stephen Holgate is Medical Research Council Clinical Professor of Immunopharmacology at the Faculty 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. Notable research contributions include the role of mast cells and their mediators in asthma and allied disorders, the regulation and pharmacology of mast cells, placing inflammation at the core of asthma pathophysiology, uncovering the role of respiratory viruses, allergens and pollutants in asthma exacerbation, the discovery of defects in innate immune responses in asthmatic airways, mechanisms of airway wall remodelling and the discovery of novel asthma susceptibility genes such as ADAM33.

His current research focuses on stratified medicine, the role of the epithelium in orchestrating asthma and the evolution of asthma across the lifecourse. His work has resulted in over 980 peer reviewed publications (H index 133), 60 Book editorships, 453 Book Chapters and Reviews, 48 Editorials, 76 Official and Government Reports. He holds an MRC programme grant focused on the pathogenesis of asthma.

 He is a Past President of the British Society of Allergy and Clinical Immunology and British Thoracic Society, was Chair of the MRC Population and Systems Medicine Board (PSMB). Stephen is Chair of Main Panel A (Medicine, Health and Life Sciences) of the UK Research Excellence Framework 2014, Chairs the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), the British Lung Foundation Research Committee, the Hazardous Substances Advisory Committee (HSAC), and from 2014, will join the Science and Innovation Strategy Board of the Natural Environment Research Council (NERC). He is Chair of the European Respiratory Society Scientific Committee, Treasurer of the World Allergy Organization and Member of the Medical Science Committee of Science Europe. In 2003 he cofounded of Synairgen a publically quoted respiratory drug development company with a particular focus on lung antiviral defense in asthma, COPD and severe viral infections.

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)
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)
FIBMS, Institute of Biomedical Science, (2009)
CSci (Hon), Science Council, (2009)

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
1998 Visiting Professor, University of Rochester USA
Brian Sproule Lecture, University of Alberta, Canada
1999 King Faisal International Prize in Medicine (Gold Medal, $200,000)
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
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
Honorary Visiting Professorship, University of Manchester (renewed 2012)
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
Almroth Wright Lecture, Imperial College
2010 David W Talmage Lectureship, Aspen Allergy Jack Selner Conference, Colorado, USA
Jeffrey Drazen Visiting Professor, Harvard Medical School, US
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
2nd Most cited European author 1998-2009 in Respiratory Research
Senior Investigator, National Institute for Health Research (NIHR)
2012 Miegunyah Distinguished Visiting Fellowship, University of Melbourne
American Thoracic Society (ATS) Recognition Award for Scientific Accomplishments (first time award was made outside N America)
Alain De Weck Honorary Lecture, VI World Asthma and COPD Forum, NY, USA
2013 Honorary Visiting Research Professorship, University of Melbourne, Australia
Longdagen Lecture 2013, Longdagen Scientific Conference, Utrecht, Netherlands
The Annual Wade Lecture, Faculty of Medicine University of Southampton
2014 The K Frank Austen Visiting Professor, Harvard University, USA
Keynote lecture, Keystone Conference on Biologics

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 and Honorary Consultant Physician, Southampton University and Foundation Trust, 1987-present

Research interests

The Pathophysiology of asthma across the lifecourse

The role of the epithelium in asthma. My research has focused on the causes of human asthma and its treatment. After establishing the key role that mast cells and other key effector cells play in triggering the acute allergic inflammatory response in asthma, I have focused my attention upon the mechanisms of disease chronicity and variability across the lifecourse. Using airway biopsies and primary cell cultures, we have established that asthma is primarily a disease of the lung epithelium that originates during fetal lung development. The disordered epithelium increases susceptibility to injury and altered repair after birth. This new concept was captured by describing sustained activation of the epithelial mesenchymal trophic unit (EMTU) in asthma. There is a dynamic communication between the epithelium and underlying mesenchyme that is established during the development of the fetal lung. We describe how varied activation of the EMTU connects the origins of asthma to its progression over time. This involves increased epithelial susceptibility to oxidant injury, impaired barrier function and reduced innate immunity. It also embraces altered mesenchymal susceptibility to promote airway remodelling such as the enhanced secretion of the metalloprotease enzyme, ADAM33, and a tendency for mesenchymal progenitor cells to adopt a contractile muscle-type phenotype.

The link between the epithelium, inflammation and remodeling. A key question that has arisen from this work is whether the “set point” for a chronic wound response by the asthmatic epithelium upon environmental injury is fundamentally altered. We have now shown that gene transcription factors involved in the differentiation of airway and alveolar epithelium in fetal lung (e.g. TTF-1, spdef, Foxa2) are also involved in asthma where their differential expression strongly promoted a mucus-secreting phenotype as functionally confirmed in the airways of mice by conditional expression or deletion of the TTF-1 gene. Moreover, the reduced epithelial TTF-1 expression in asthma not only increased mucus secretion, but also the capacity of the airways to express allergic-type inflammatory and tissue remodelling profiles in response to allergen exposure. These experiments provide strong additional support for the view that, through the EMTU, the airway epithelium plays a crucial role in orchestrating multiple cellular events of asthma.

While remodelling of the airways in asthma could occur secondary to chronic inflammation, anti-inflammatory drugs (such as corticosteroids) have limited effect on this component. We now propose that distortion of a hypersensitive and chronically damaged epithelium by repeated bronchoconstriction is also capable of driving remodelling, possibly as an initial protective response. We found that the the early asthmatic response provoked by inhaled allergen (inflammatory stimulus) or methacholine (non-inflammatory stimulus) produced similar increases in airway remodelling. As predicted, only allergen triggered eosinophil influx into the airways in association with the inflammatory response of the late asthmatic response. Prevention of methacholine-induced bronchoconstriction by prior administration of the inhaled2-agonist (salbutamol) completely inhibited the indices of remodelling. This indicates that repeated narrowing of asthmatic airways per se provides a sufficient stimulus for inducing “mechanotransductive” airway remodelling.

Mechanisms of the asthma exacerbation. A major cause of asthma morbidity and death is the exacerbation in which deterioration in disease control occurs over several days. Although allergen exposure is one cause of disease exacerbation, in real life this accounts for only a small proportion of events. On the basis of clinical anecdote many asthma exacerbations appeared to be precipitated by respiratory viral infections. To obtain concrete evidence for this, we first established novel PCR-based methods for the detection of common cold human rhinoviruses (RV). Viral detection was then applied to longitudinal cohort studies to reveal that detection of respiratory viruses in nasopharyngeal secretions was closely linked to asthma exacerbation and its seasonal variation both in children (>85%) and adults (>65%), with RV dominating.

We were the first to establish causality by controlled nasal infection of asthmatics with RV16 precipitating clinical and physiological features of exacerbation driven by mixed eosinophilic and lymphocyte inflammation of the lower airways. A key question was why asthmatic airways are so susceptible to usually innocuous common cold viruses? Controlled nasal infection with RV16 to revealed preferential infection of the asthmatic lower airway epithelium. In order to determine if viral responses of the asthmatic epithelium differed from that of normals, epithelial cell cultures infected with RV16 were developed. While epithelial cells from normal subjects could effectively inhibit viral replication and eliminate remaining virus through activation of programmed cell death (apoptosis), those derived from asthmatic airways not only enabled the virus to survive, but also facilitated viral replication leading to cytotoxic cell death, inflammatory mediator release and enhanced virus shedding. We have shown that this asthma-related defect was due to impaired signalling by the microsomal danger recognition receptor, toll-like receptor 3 (TLR3), following interaction with viral double stranded RNA. The consequence of this was reduced (IFN)- mediated anti-viral defense. This defect in IFN production could in large part explained by enhanced epithelial production of TGF-β and represents yet a further consequence of EMTU activation in asthma. Of great significance was our finding that full anti-viral defense could be restored to the asthmatic epithelium by adding back a low concentration of IFNwhereas under natural conditions of virus infection, the defective local IFN induction was compensated by a large systemic innate TLR/IFN immune response and a weaker adaptive immune response.

In order to translate these findings into the clinic we first showed that inhaled IFN-1a could activate the airway anti-viral pathways in asthma. We have now completed a successful Phase 2 clinical trial showing that inhaled recombinant human IFN-1a given at the start of a common cold in patients with severe asthma could fully restore protection against viral-related exacerbations as well as reduce viral shedding (http://www.synairgen.com/).

Rethinking the cause and pathophysiology of asthma. These observations are leading to a fundamental re-evaluation of asthma pathogenesis. Rather than allergic inflammation being the prime abnormality, our work places the airway epithelium at the centre of disease pathogenesis by, serving as the orchestrator of inflammatory and remodelling responses over the lifecourse. The engagement of different causative molecular pathways leads to disease heterogeneity which is reflected in the variable response to therapeutics in accordance with the relative contribution of that pathway to the overall disease manifestation. This forms the basis for a more stratified or personalized approach to treatment which is especially important for the highly targeted new biologics.

Proposed interaction between early life virus infection and allergen exposure in the induction of asthma in genetically susceptible children
Proposed interaction
Diagramatic representation of the epithelial mesenchumal trphic unit in asthma drive by the release of epithelial derived growth factors
Diagramatic representation

Department(s)

Clinical and Experimental Sciences

Affiliate Department(s)

Respiratory and allergy Research group

As an MRC Research Professor I oversee a large research team pursuing the mechanisms of asthma, identifying novel therapeutic targets and undertake experimental medicine and clinical trials in asthma.

Faculty of Medicine

Member, Faculty of Medicine’s Strategy Oversight Group, 2011-present

In addition: current responsibilities at a national level include:

MEDICAL RESEARCH COUNCIL

1. Chairman, MRC Population and Systems Medicine Board, 2007-present
2. Member, MRC Strategy Board, 2007-present
3. Chair of Grant Review Panel for Stratified Medicine, 2011
4. Chair of CFS/ME Expert Group
5. Chair of Disease Cohorts Oversight Group

GOVERNMENT DEPARTMENTS

1. Chair, Research Excellence Framework (REF) Main Panel A: Medicine, Health and Life Sciences, 2010-14
2. Chair (10 yrs), now Member of Department of Health Committee on the Medical Effects of Air Pollutants (COMEAP), 1990-present
3. Member, now Chairman of Department of Environment and Rural Affairs Expert Panel on Air Quality Standards (EPAQS), incorporated as a subpanel of COMEAP in 2008
4. Member, Food Standards Agency Advisory Committee on Novel Foods and Processes, 2005-present
5. Chair, DEFRA Advisory Committee on Hazardous Substances, 2008-present
6. Member, DH/NIHR Standing Committee on Policy Commissioned Research, 2011-present

NATIONAL & INTERNATIONAL ACADEMIC ATIVITIES

1. Member, Council (until 1994), Secretary General (2007), President Elect (2010), Collegium International Allergologicum (CIA), 1990 – present
2. Member, Executive Board of World Allergy Organisation (WAO), 2007- present
3. Chairman, Merck International Respiratory Advisory Board, 1998-present.
4. Member of Council, Academy of Medical Sciences, 2010–present.
5. Member, Strategic Advisory Board of the NNUHT & Norwich Medical School Clinical Academic Initiative, 2011-present
6. Chair, Republic of Ireland HRCG and Charities Joint Research Board, 2011-present
7. Member, Advisory Board of the European Centre of Environment and Human Health, University of Exeter, 2011-present
8. Member of the University of East Anglia Strategic Group for the Development of Integrated Science 2011-present

Postgraduate Supervision

Currently Supervised

PhD - 2 students

Supervised to successful completion

MSc - 3 students
PhD - 31 students
DM - 29 Students

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Articles

Book Chapters

Conferences

Reports

Review

Teaching is restricted to postgraduate activities both in the UK and overseas.

This takes the form of keynote lectures, plenary lectures and talks on specialist areas of asthma allergic diseases, pollution and translational medicine including participation in postgraduate courses.

Educational activities also extend to editorships of major texts in asthma, allergy and respiratory medicine. Examples include “Allergy” (4 editions) and “Middleton’s Allergy:Principles and Practice” (4 editions) (see below).
Editor of Clinical and Experimental Allergy (25 years to 2009) and current Associate Editor, Clinical Science.

Allergy
Principles and Practice
Middleton's Allergy
Professor Stephen Holgate
Tel: (0)23 8120 6960 Fax: (0)23 8070 1771 Email: sth@southampton.ac.uk

Room Number: SGH/LF102/MP810

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