The Helicobacter pylori-induced regulatory T-cell response

Lead Research Organisation: University of Nottingham
Department Name: Academic Division of Child Health

Abstract

The bacterium (germ) Helicobacter pylori is the main cause of stomach and duodenal ulcers and of stomach cancer. The bacterium is common, but most people who have it never develop either of these conditions and stay entirely well. The infection induces an immune response but this does not usually kill the bacteria, which may persist in the stomach lining for life unless antibiotics are administered. Published data suggest that differences in the type of immune response to H. pylori could protect against or favour the development of ulcers and gastric cancer. Our recent research indicates that immune cells of a suppressive nature (regulatory T-cells) may help to prevent ulceration by reducing inflammation, and these cells might also help the bacteria to remain in the stomach. Our experiments showed that people with peptic ulcers have low levels of regulatory T-cells, and this possibly means that there are insufficient numbers of these cells to prevent the development of severe inflammation of the stomach lining. We now need to prove if reducing the regulatory T-cell response does change the amount of inflammation, by infecting mice and giving a treatment to block their suppressive activity. It is important for us to know more about these suppressive T-cells, how they act, and what induces their production during the immune response. If we have a good understanding of this, we may be able to identify those at risk of developing disease in the future and design effective vaccines. If the work is successful we plan to make the results widely available. Both the University of Nottingham and the MRC inform the press of successful research.

Technical Summary

Helicobacter pylori (Hp) colonizes the stomachs of approximately half the world?s population and is associated with peptic ulceration and gastric malignancy. Hp usually establishes an asymptomatic infection, and provokes a vigorous but ineffective immune response which permits life-long persistence in the gastric mucosa. This implies that inflammation is modulated, and the mechanisms of immune subversion remain unclear.
It was previously reported that Hp-induced pathology is determined by the acquired immune response to infection. In recent observational studies, we have shown for the first time that certain human Treg responses are associated with protection from Hp-mediated peptic ulcer disease. We therefore hypothesise that Hp expresses factors which drive Treg responses, resulting in the evasion of immunity and promoting persistence in the gastric mucosa.
For this project, we wish to characterise the regulatory T-cells in the blood and gastric mucosa of H. pylori-infected donors and investigate their antigenic specificity. We will carry out interventional experiments in mice to determine if disease severity is indeed determined by the level of the Treg response, and examine the effects of regulatory T-cell-inducing bacterial factors in vivo. These studies will allow us to discover whether differences between strains influence the response elicited, and if this might explain differences in disease severity and persistence of the infection. Understanding the factors that allow the bacteria to persist in the stomach may lead to future advances in the development of effective vaccines.

Publications

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Amberbir A (2014) Exposure to Helicobacter pylori infection in early childhood and the risk of allergic disease and atopic sensitization: a longitudinal birth cohort study. in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

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Amberbir A (2011) Effects of Helicobacter pylori, geohelminth infection and selected commensal bacteria on the risk of allergic disease and sensitization in 3-year-old Ethiopian children. in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

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Atherton JC (2009) Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. in The Journal of clinical investigation

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Robinson K (2017) The Human Stomach in Health and Disease: Infection Strategies by Helicobacter pylori. in Current topics in microbiology and immunology

 
Description CRUK Project Grant
Amount £298,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2009 
End 12/2012
 
Description Clinical Research Training Fellowship
Amount £183,201 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2011 
End 12/2014
 
Description Institute of Infection, Immunity & Inflammation Research Funding Bid
Amount £5,820 (GBP)
Organisation University of Nottingham 
Department Centre for Biomolecular Sciences
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2008 
End 12/2008
 
Description MRC Clinical Research Training Fellowship
Amount £192,810 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2008 
End 08/2013
 
Description MRC Clinical Training Fellowship - Joanna Stephens
Amount £194,730 (GBP)
Funding ID MR/N001826/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2016 
End 09/2021
 
Description MRC PhD Studentship
Amount £69,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2016 
End 03/2020
 
Description MRC PhD Studentship
Amount £48,600 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2008 
End 09/2011
 
Description NIHR Biomedical Research Unit
Amount £600,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Unit, Nottingham University Hospitals NHS Trust
Sector Learned Society
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2012 
End 12/2017
 
Description NUH Charity Pump Priming Funds
Amount £15,000 (GBP)
Organisation Nottingham University Hospitals NHS Trust 
Department Nottingham University Hospitals Charity
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2011 
End 05/2014
 
Description Nottingham Molecular Pathology Node
Amount £79,983 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2015 
End 09/2019
 
Description PhD Studentship
Amount £48,000 (GBP)
Organisation University of Nottingham 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2009 
End 10/2012
 
Description PhD studentship
Amount £54,668 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2010 
End 10/2013
 
Description Pump Priming Award
Amount £37,000 (GBP)
Organisation University of Nottingham 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2010 
End 12/2011
 
Description Strategic Funding Initiative
Amount £35,000 (GBP)
Organisation University of Nottingham 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2009 
End 07/2009
 
Description Strategic Skills Award
Amount £15,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2010 
End 10/2013
 
Description The University of Nottingham Pump priming for transgenic mice
Amount £20,000 (GBP)
Organisation University of Nottingham 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2011 
End 07/2013
 
Description University of Nottingham pump priming award
Amount £23,639 (GBP)
Organisation University of Nottingham 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2016 
End 07/2016
 
Description Wellcome Trust VIP Award
Amount £13,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Strategic Award
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 05/2013 
End 12/2013
 
Title Nottingham Helicobacter Collection 
Description Archive of H. pylori isolates, blood and tissue together with a database of anonymised clinical data. 
Type Of Material Biological samples 
Provided To Others? No  
Impact Award of CRUK project grant, Nottingham Molecular Pathology Node award 
 
Description Developing blood- and serum-based diagnostic tests for H. pylori and predictive markers of disease 
Organisation University of Nottingham
Department Nottingham Digestive Diseases Centre
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Using recombinant proteins from H. pylori as the basis of serological tests to non-invasively diagnose the virulence factors of the colonising strain. Analysing blood samples for biomarkers correlating with gastro-duodenal disease or lack of disease.
Collaborator Contribution Provision of serum from infected patients
Impact Further funding from this as part of the MRC/EPSRC Nottingham Pathology Node, working with mathematicians to model complex bacterial and host parameters in order to determine disease predictive biomarkers.
Start Year 2012
 
Description Developing multi-parameter Chipcytometry 
Organisation Hannover Medical School
Department Zellkraftwerk
Country Germany, Federal Republic of 
Sector Academic/University 
PI Contribution Optimisation of sample preparation of gastric mucosal tissue and blood leukocytes for >30 parameter staining and chipcytometry
Collaborator Contribution Optimisation of staining. Staining and scanning of chips.
Impact No outputs as the approach turned out not to be suited to our samples
Start Year 2013
 
Description H. pylori induced modulation of beta defensin 1 expression 
Organisation Friedrich-Alexander University Erlangen-Nuremberg
Department School of Life Sciences Friedrich-Alexander
Country Germany, Federal Republic of 
Sector Academic/University 
PI Contribution Study of beta defensin responses to H. pylori infection in vitro and in vivo
Collaborator Contribution Provision of Helicobacter pylori mutant strains. Intellectual input to the project.
Impact Patel et al. (2013) Helicobacter pylori downregulates expression of human ß-defensin 1 in the gastric mucosa in a type IV secretion-dependent fashion. Cell Microbiol. Jul 21. doi: 10.1111/cmi.12174. Oral presentation at the SGM Autumn Conference 2013, which was featured in a press release http://www.sgm.ac.uk/en/media_centre/press-releases.cfm/stomach-bacteria-switch-off-human-immune-defences-to-cause-disease
Start Year 2013
 
Description Helicobacter and multiple sclerosis 
Organisation Karolinska University Hospital
Country Sweden, Kingdom of 
Sector Hospitals 
PI Contribution Recently developed a collaboration to allow a multi-centre analysis of the association between Helicobacter pylori infection and multiple sclerosis. MRC IMPACT DTP student and an MRC Clinical Training Fellow working on this project Currently have a grant submitted to the MS Society
Collaborator Contribution Provision of data and serum samples
Impact No outputs yet as this is a new collaboration.
Start Year 2015
 
Description Helicobacter and multiple sclerosis 
Organisation University of Copenhagen
Department Department of Neurology, Psychiatry and Sensory Sciences
Country Denmark, Kingdom of 
Sector Academic/University 
PI Contribution Recently developed a collaboration to allow a multi-centre analysis of the association between Helicobacter pylori infection and multiple sclerosis. MRC IMPACT DTP student and an MRC Clinical Training Fellow working on this project Currently have a grant submitted to the MS Society
Collaborator Contribution Provision of data and serum samples
Impact No outputs yet as this is a new collaboration.
Start Year 2015
 
Description Helicobacter pylori and multiple sclerosis 
Organisation University of Nottingham
Department School of Clinical Sciences Nottingham
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Animal model studies to determine if H. pylori protects against experimental autoimmune encephalopathy. Clinical studies analysing H. pylori infection status of patients, MS symptoms, and the cellular immune response
Collaborator Contribution Expertise with the EAE model of multiple sclerosis. Access to serum from MS patients.
Impact Multi-disciplinary collaboration, combining gastroenterology with clinical neurology and immunology in humans and mouse models. Resulted in a research publication and a book chapter as outputs. MRC Clinical Training Fellow and MRC IMPACT DTP PhD student continuing this work. Funding applied for from MS Society.
Start Year 2010
 
Description Helicobacter pylori infection and allergy 
Organisation Addis Ababa University
Country Ethiopia, Federal Democratic Republic of 
Sector Academic/University 
PI Contribution Investigation of whether H. pylori-induced regulatory T-cells contribute to the reported protective effects against allergy and asthma. Investigation of whether H. pylori eradication has an impact on the number and type of Treg cells, and on allergy and asthma.
Collaborator Contribution Expertise with mouse models for allergy, assays for human allergen-specific IgE Collaborative work on human H. pylori infections, regulatory T-cells and allergy. Forged invaluable links with the Biomedical Research Unit in Respiratory Medicine (University Hospital, Nottingham).Child cohort study on infections and allergy/asthma - results show that H. pylori has a strong protective effect Enabled us to obtain a research funding award from the Biomedical Research Unit in Respiratory Medicine (University Hospital, Nottingham).
Impact Papers: AMBERBIR, A, MEDHIN, G, ERKU, W, ALEM, A, SIMMS, R, ROBINSON, K, FOGARTY, A, BRITTON, J, VENN, A and DAVEY, G, 2011. Effects of Helicobacter pylori, geohelminth infection and selected commensal bacteria on the risk of allergic disease and sensitization in 3-year-old Ethiopian children. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. ROBINSON, K. and BRADLEY, J. E., 2010. The allergy epidemic: can helminths supply the antidote?. Clinical & Experimental Allergy, 40, 1586-9. 2 further papers currently in preparation. Abstracts presented at the American Thoracic Association Conference. Enabled us to be awarded an MRC DTA PhD studentship from the University of Nottingham. Invited speaker at UEGW conference, Barcelona, Oct 2010. Multidisciplinary project, combining gastroenterology, immunology, epidemiology, parasitology, bacteriology and work with animal models.
Start Year 2008
 
Description Helicobacter pylori infection and allergy 
Organisation University of Nottingham
Department School of Biomedical Sciences Nottingham
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Investigation of whether H. pylori-induced regulatory T-cells contribute to the reported protective effects against allergy and asthma. Investigation of whether H. pylori eradication has an impact on the number and type of Treg cells, and on allergy and asthma.
Collaborator Contribution Expertise with mouse models for allergy, assays for human allergen-specific IgE Collaborative work on human H. pylori infections, regulatory T-cells and allergy. Forged invaluable links with the Biomedical Research Unit in Respiratory Medicine (University Hospital, Nottingham).Child cohort study on infections and allergy/asthma - results show that H. pylori has a strong protective effect Enabled us to obtain a research funding award from the Biomedical Research Unit in Respiratory Medicine (University Hospital, Nottingham).
Impact Papers: AMBERBIR, A, MEDHIN, G, ERKU, W, ALEM, A, SIMMS, R, ROBINSON, K, FOGARTY, A, BRITTON, J, VENN, A and DAVEY, G, 2011. Effects of Helicobacter pylori, geohelminth infection and selected commensal bacteria on the risk of allergic disease and sensitization in 3-year-old Ethiopian children. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. ROBINSON, K. and BRADLEY, J. E., 2010. The allergy epidemic: can helminths supply the antidote?. Clinical & Experimental Allergy, 40, 1586-9. 2 further papers currently in preparation. Abstracts presented at the American Thoracic Association Conference. Enabled us to be awarded an MRC DTA PhD studentship from the University of Nottingham. Invited speaker at UEGW conference, Barcelona, Oct 2010. Multidisciplinary project, combining gastroenterology, immunology, epidemiology, parasitology, bacteriology and work with animal models.
Start Year 2008
 
Description Helicobacter pylori infection and allergy 
Organisation University of Nottingham
Department School of Medicine
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Investigation of whether H. pylori-induced regulatory T-cells contribute to the reported protective effects against allergy and asthma. Investigation of whether H. pylori eradication has an impact on the number and type of Treg cells, and on allergy and asthma.
Collaborator Contribution Expertise with mouse models for allergy, assays for human allergen-specific IgE Collaborative work on human H. pylori infections, regulatory T-cells and allergy. Forged invaluable links with the Biomedical Research Unit in Respiratory Medicine (University Hospital, Nottingham).Child cohort study on infections and allergy/asthma - results show that H. pylori has a strong protective effect Enabled us to obtain a research funding award from the Biomedical Research Unit in Respiratory Medicine (University Hospital, Nottingham).
Impact Papers: AMBERBIR, A, MEDHIN, G, ERKU, W, ALEM, A, SIMMS, R, ROBINSON, K, FOGARTY, A, BRITTON, J, VENN, A and DAVEY, G, 2011. Effects of Helicobacter pylori, geohelminth infection and selected commensal bacteria on the risk of allergic disease and sensitization in 3-year-old Ethiopian children. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. ROBINSON, K. and BRADLEY, J. E., 2010. The allergy epidemic: can helminths supply the antidote?. Clinical & Experimental Allergy, 40, 1586-9. 2 further papers currently in preparation. Abstracts presented at the American Thoracic Association Conference. Enabled us to be awarded an MRC DTA PhD studentship from the University of Nottingham. Invited speaker at UEGW conference, Barcelona, Oct 2010. Multidisciplinary project, combining gastroenterology, immunology, epidemiology, parasitology, bacteriology and work with animal models.
Start Year 2008
 
Description Immunological effects of H. pylori VacA 
Organisation University of Nottingham
Department Nottingham Digestive Diseases Centre
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Investigating the role of different forms of the vacuolating cytotoxin A in cololonisation and carcinogenesis.
Collaborator Contribution Provision of bacterial mutant strains
Impact Submission of application for a Newton Fellowship to work on VacA and autophagy. MRC Clinical Training Fellowship to continue this work.
Start Year 2012
 
Description An article for Reuters Health News 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact An article was written on our research for Reuters Health News and published on their website http://www.clpmag.com/reuters_article.asp?id=20081010clin030.html
Year(s) Of Engagement Activity 2008
URL http://www.clpmag.com/reuters_article.asp?id=20081010clin030.html
 
Description Magazine article for International Innovation 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/parliamentarians
Results and Impact Contacted by external companies. Invited to give talk.

More interest in our work
Year(s) Of Engagement Activity 2014
 
Description Member of scientific committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 8th, 9th & 10th International Workshop on Pathogenesis and Host Response in Helicobacter Infections, Helsingor, Denmark. Member of scientific committee, session chair, prize judge

Invited to write review articles, examine and co-supervise research students.
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
 
Description Microbiology Today article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Wrote an article on Helicobacter pylori infections in childhood for the SGM magazine Microbiology Today. This highlighted some of the findings of my research. The magazine is circulated mainly to academic microbiologists, but also to schools, policitians, and SGM members in industry

None
Year(s) Of Engagement Activity 2012
 
Description Research Showcase 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Poster Presentation
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Selected amongst top 50 postgraduate student submissions for poster presentation judged by a panel made up of prominent local members of the public and communications directors from the Research Councils. Confirmed judges so far include Philip Pothen (Head of Communications, AHRC), Terry O'Connor (Director of Communications, STFC), Atti Emecz (Director, Communications & Information, EPSRC), Saskia Walcott (Head of Communications and Public Engagement, ESRC) and Ken Hollywood (Head of Research Knowledge Services, British Geological Survey) .

The student who presented at the event in 2010 was selected to present at the SET for Britain Event at the House of Lords in 2011.
Year(s) Of Engagement Activity 2010,2011,2012
 
Description SET for Britain Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Policymakers/parliamentarians
Results and Impact My previous MRC-funded PhD student Sapna Patel was accepted to present her research findings in poster form and in discussion with MPs and representatives from the Society of Biology and Industry.

The student's CV was strengthened
Year(s) Of Engagement Activity 2011
 
Description SGM Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Katherine Cook was invited to present the data at the SGM Autumn conference on 2nd Sept 2013. In advance of this the SGM Media office contacted us to ask if they could feature our paper.

The press release was featured on 15 other websites, including Science Daily http://www.sciencedaily.com/releases/2013/09/130902101712.htm, some health insurance websites, and cancer and health interest groups.
Year(s) Of Engagement Activity 2013
URL http://www.sgm.ac.uk/en/media_centre/press-releases.cfm/stomach-bacteria-switch-off-human-immune-def...
 
Description Spotlight on Microbiology 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Feature on microbiology in The Society of Biology journal The Biologist including an interview with myself as a microbiologist.

None
Year(s) Of Engagement Activity 2012