Regulation of inflammation by endogenous danger signals

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Rheumatoid arthritis (RA) is an inflammatory disorder that causes the immune system to attack the joints. It is a disabling and painful condition that leads to loss of mobility due to joint destruction. The incidence of RA is 30 cases per 10,000 people; there are more than 350,000 sufferers in the UK alone. RA is a progressive disease, after 5 years ~33% of patients are unable to work, and it shortens life expectancy by 5-10 years.

Inflammation is the first response of the immune system to infection and injury.
It is activated by infectious agents and by molecules made by the body upon injury, known as ‘danger signals’. Cells flood the affected area and release cytokines including TNF?, IL-6 and IL-8. Cytokines fight infection and promote repair by removing infectious agents, and degrading dead/damaged tissue. Normally, cytokine activity is tightly controlled; after infection or injury is resolved they are no longer made.

Autoimmune diseases such as RA result from chronic or ongoing inflammation. What triggers the immune response in RA is unknown but the joint becomes inflamed. Here, cytokines cause degradation of healthy joint tissue. This injury stimulates continued inflammation and a vicious cycle is created that leads to extensive destruction of the joint.

Current treatments of RA stop joint destruction by inhibiting TNF? and IL-6 action. However, repeated treatments are required, making it expensive, and this approach doesn’t lead to permanent remission. Suppressing the immune response at this level also renders the patient unable to fight infection. Thus, a major goal of our studies is to develop new therapies for RA.

One group of molecules, called damage associated molecular patterns or DAMPs, are made by the body in response to tissue injury. Levels usually return to normal when repair is complete, however, large amounts are continually produced in autoimmune diseases including RA. We have shown that specific DAMPs stimulate TNF?, IL-6 -8 synthesis in isolated cells. We hypothesize that their persistence in RA drives excessive cytokine production.

This project aims to determine if inhibition of specific DAMPs in human RA joint tissue prevents cytokine production and whether mice that don’t express these DAMPs are protected from experimentally induced RA. These experiments reveal if blockade of DAMP action will be of clinical benefit. To design strategies that prevent DAMP action we will investigate how these molecules interact with cells to cause cytokine production. Thus we hope to limit excessive tissue damage in RA without compromising patient response to infection.

Technical Summary

Tenascin-C is an extracellular matrix protein that is specifically and transiently induced upon tissue injury; levels return to normal after repair is complete. Persistent expression of tenascin-C occurs in chronic non-healing wounds and in autoimmune diseases including rheumatoid arthritis (RA). We have shown that tenascin-C induces the synthesis of pro-inflammatory cytokines in primary human macrophages and RA synovial fibroblasts. However, the precise role of tenascin-C in vivo is not known. This study aims to (1) determine if persistent expression of tenascin-C contributes to the pathological progression of RA and (2) to identify the mechanism by which tenascin-C interacts with and signals to cells to mediate an inflammatory response.

Publications

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Bavan L (2011) MicroRNA epigenetics: a new avenue for wound healing research. in BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy

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Midwood K (2013) Startups on the menu. in Nature biotechnology

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Midwood KS (2009) Targeting Toll-like receptors in autoimmunity. in Current drug targets

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Midwood KS (2009) The role of tenascin-C in tissue injury and tumorigenesis. in Journal of cell communication and signaling

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Midwood KS (2011) Advances in tenascin-C biology. in Cellular and molecular life sciences : CMLS

 
Description AICR project grant
Amount £250,000 (GBP)
Organisation World Cancer Research Fund 
Sector Charity/Non Profit
Country Global
Start 02/2016 
End 02/2018
 
Description Arthritis Research UK Senior Fellowship
Amount £807,821 (GBP)
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 03/2018
 
Description Asthma UK PhD Studentship
Amount £98,000 (GBP)
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 09/2018
 
Description BSMB travel bursary
Amount £200 (GBP)
Organisation British Society for Matrix Biology (BSMB) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2010 
End 03/2010
 
Description Healing Foundation project
Amount £25,000 (GBP)
Organisation University of Manchester 
Department Healing Foundation (Charity for people with disfigurement and visible loss of function)
Sector Charity/Non Profit
Country United Kingdom
Start 03/2010 
End 09/2010
 
Description ICI travel bursary/International Comgress of Immunology
Amount £1,000 (GBP)
Organisation International Congress of Immunology (ICI) 
Sector Academic/University
Country Global
Start 02/2009 
End 02/2009
 
Description Imperial Innovations seed funding
Amount £15,000 (GBP)
Organisation Imperial Innovations 
Sector Private
Country United Kingdom
Start 10/2009 
End 09/2010
 
Description Indigix project
Amount £120,526 (GBP)
Organisation Indigix ltd 
Sector Private
Country United Kingdom
Start 04/2011 
End 04/2012
 
Description MRS studentship
Amount £205,467 (GBP)
Organisation Medical Research Scotland 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2019
 
Description Nascient Research Collaboration
Amount £475,000 (GBP)
Organisation Nascient ltd 
Sector Private
Country United Kingdom
Start 02/2014 
End 02/2017
 
Description Novimmune project
Amount £59,410 (GBP)
Organisation Novimmune, Geneva 
Sector Private
Country Switzerland
Start 01/2011 
End 07/2011
 
Description Respivert
Amount £222,620 (GBP)
Organisation Johnson & Johnson 
Sector Private
Country United States
Start 09/2011 
End 08/2013
 
Description Royal College of Surgeons small grant
Amount £4,500 (GBP)
Organisation Royal College of Surgeons of England 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2009 
End 01/2010
 
Title recombinant TNC domains 
Description LPS free recombinant proteins comprising each region of the large matrix molecule tenacsin-C 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Enabled dissection of pro-inflammatory mechanism of action of tenascin-C 
 
Description Assays for diagnosing inflammatory diseases 
Organisation University of Edinburgh
Department The Roslin Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of tenascin-C biology
Collaborator Contribution Murine models of inflammation
Impact Successful studentship application from MRS, student started Oct 2015
Start Year 2014
 
Description IL33 promoter analysis 
Organisation Oslo University Hospital
Department Department of Pathology
Country Norway 
Sector Hospitals 
PI Contribution Analysis of the promoter region of the Il-33 gene
Collaborator Contribution Discovered transcriptional regulation of IL-33 gene during inflammation.
Impact 19) Sundlisæter, E., Edelmann, R. J., Hol, J., Sponheim, J., Küchler, A. M., Weiss, M., Udalova, I.A., Midwood, K. S., Kasprzycka, M., Haraldsen, G. (2012) The Alarmin Interleukin-33 is a Notch Target in Quiescent Endothelial Cells. American Journal of Pathology 181(3):1099-111.
Start Year 2011
 
Description Transcriptional regulation of endogenous danger signals 
Organisation University of Oxford
Department Kennedy Institute of Rheumatology
Country United Kingdom 
Sector Academic/University 
PI Contribution generation of new data, access to materials and intellectual input
Collaborator Contribution The use of newly generated reagents and novel techniques with which to study how the expression of tenasinc-C is regulated
Impact This project has generated new data that has been recently published and a grant proposal arising from the data that is currently under review.
Start Year 2008
 
Description Tumor immunology 
Organisation Cochin Institute
Department INSERM U1016
Country France 
Sector Academic/University 
PI Contribution Analysis of tumor cell activation
Collaborator Contribution In vivo models of tumor progression
Impact Successful grant application, post doc recruited and project commenced Feb 2016
Start Year 2013
 
Description Viral exacerbations of asthma and the matrix 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of tenascin-C immune function
Collaborator Contribution in vivo and ex vivo models of airway epithelial cell response to rhinoviral infection and asthma
Impact Successful PhD studentship application from Asthma UK, student commenced Oct 2015
Start Year 2013
 
Title BIOLOGICAL MATERIALS AND USES THEREOF 
Description Activation of FBG domain of tenascin-C of TLR4 drives persistent inflammation in models of RA 
IP Reference P45612EP-EPO 
Protection Patent granted
Year Protection Granted 2013
Licensed Yes
Impact n/a
 
Title Biological Materials and Uses Thereof 
Description Tenasicn-C drive Th17 cell polarization in RA 
IP Reference US 61/718,898 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact Allowed to lapse
 
Title Tenascin-C regulates TLR4-mediated immunity via microRNA-155 
Description Endogenous control of immunity against infection: tenascin-C regulates TLR4-mediated inflammation via microRNA-155. 
IP Reference WO2014033463 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact Patent discontinued and case closed.
 
Company Name Nascient 
Description Nascient is a spin out company whose sole platform is to develop antibodies that block the pro-inflammatory activity of tenascin-C. 
Year Established 2012 
Impact n/a
 
Description Imperial News 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I was interviewed by Imperial press about the impact of our work on finding new treatments for arthritis for an article in the College newsletter.

The article was published on line and covered by a numer of news sites world wide:


Coverage:





United Press International


http://www.upi.com/Science_News/2009/07/02/Rheumatoid-arthritis-signal-molecule-found/UPI-51611246563098/





Science Business


http://bulletin.sciencebusiness.net/ebulletins/showissue.php3?page=/548/art/14312





Science Daily


http://www.sciencedaily.com/releases/2009/06/090628171953.htm





Medical News Today


http://www.medicalnewstoday.com/articles/156219.php





Newspost Online


http://www.newspostonline.com/health/scientists-uncover-new-trigger-for-chronic-inflammation-in-rheumatoid-arthritis-2009070262088





Innovations Report


http://www.innovations-report.com/html/reports/medicine_health/trigger_chronic_inflammation_rheumatoid_arthritis_135038.html





Asia News International (no link)
Year(s) Of Engagement Activity 2009
 
Description Nature Sci Cafe 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Industry/Business
Results and Impact I was chosen as one of 3 speakers from Europe by the Nature Editoral Board to present to 50 representatives from pharmaceutical companies and venture capitalists, followed by a reception and dinner.

Potential new collaborations in pharma and drug discovery.
Year(s) Of Engagement Activity 2009
 
Description On line interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Online interview for undergraduate students discussing the data from our NM paper on new option for treating RA.

Many e mails from students and sufferers of RA asking for more information
Year(s) Of Engagement Activity 2009
 
Description SET for Britain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Local MP contacted to inform about our work, ~45 politicians attended talk in parliament, sparking discussion afterwards

n/a
Year(s) Of Engagement Activity 2010