Manipulating the repair response by vascular progenitor cells; a strategy for preventing and treating chronic rejection

Lead Research Organisation: King's College London
Department Name: Immunology Infection and Inflam Diseases

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

Organ transplantation is a therapeutic success, but allografts fail prematurely, rarely sustaining recipients for their natural lifespan. A major problem is chronic rejection (CR) manifesting in many organs as transplant arteriosclerosis (TA), in which (as in other types of vascular injury) intimal hyperplasia (IH) leads to progressive ischaemia and fibrosis. There is currently no effective treatment for TA or CR. The basic hypothesis for this proposal is that each of us has vascular progenitor (VP) cells capable of repairing damaged blood vessels, but in TA they are inhibited from doing so by inflammatory factors generated by the immune response. The hypothesis arises directly from our current MRC-funded work, in which we have shown that IH can be completely inhibited by preventing the generation or actions of thrombin on the surface of bone marrow-derived VP. These manipulations lead to regeneration of vessel wall architecture, even in the face of an ongoing alloimmune response. We have concluded that thrombin is a critical factor determining how VP respond to repair cues. We postulate that other factors known to impact on TA, such as the ?danger signal? high mobility group box-1 protein, interferon gamma and nitric oxide, do so by influencing the responsiveness of VP to thrombin, thereby affecting the recruitment, phenotype or function of these cells, independently of effects on the alloimmune response. The goal is to define how these factors enhance or inhibit regenerative repair by VP. The specific aims are to; 1) Define the influence of IFN gamma, NO and HMGB-1 on the phenotype, mobilization and recruitment of VP subpopulations after vascular injury; 2) Link the influence of these factors to thrombin generation or responsiveness; 3) Demonstrate that the neointimal disease in TA is due to phenotypic or functional changes in VP independently of the alloimmune injury. These studies will define, for the first time, the relationships between immune effector and vascular repair mechanisms and establish the foundation for a novel therapeutic strategy to prevent or treat CR, based on manipulating the responsiveness of VP. The results of this study will be used directly to influence the design of therapeutic trials in the dialysis and renal transplant populations at the Hammersmith, in whom clinical research into the biology of circulating VP has already begun.

Publications

10 25 50
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Armstrong-James D (2012) Renal allograft recipients fail to increase interferon-? during invasive fungal diseases. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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Barnett AN (2014) Tailored desensitization strategies in ABO blood group antibody incompatible renal transplantation. in Transplant international : official journal of the European Society for Organ Transplantation

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Barnett AN (2013) The use of eculizumab in renal transplantation. in Clinical transplantation

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Barnett N (2011) B cells in renal transplantation: pathological aspects and therapeutic interventions. in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

 
Description Co-opted onto BTS council to represent Basic Science
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Frontiers in Transplantation Course
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description International Advisory Committee for the World Transplant Congress 2014
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Description Member of Faculty, World Transplant Congress 2014
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Scientific Advisory Panel, BTS annual Meeting 2012
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Capital Bid
Amount £1,690,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 09/2015
 
Description Determining the importance and predictive value of T and B lymphocyte alloreactivity in the progression of chronic antibody mediated rejection - an analysis of samples from a UK randomised controlled trial.
Amount £179,840 (GBP)
Funding ID RP3/2011 
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2012 
End 01/2015
 
Description Dysfunctional mobilisation of vascular progenitor cells post-kidney transplantation and post-rejection as a correlate to progressive loss of allograft function (Guy's & St Thomas' Charity)
Amount £180,200 (GBP)
Organisation Guy’s & St Thomas’ Charity 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description EME programme award
Amount £2,300,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2013 
End 03/2019
 
Description KRUK Clinical Training Fellowship to Dr Philippa Dodd
Amount £258,741 (GBP)
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2014 
End 08/2017
 
Description King's Health Partners Challenge Fund
Amount £46,667 (GBP)
Funding ID R160405 
Organisation King’s Health Partners 
Sector Academic/University
Country United Kingdom
Start 06/2016 
End 05/2017
 
Description King's Worldwide Partnership Fund
Amount £1,984 (GBP)
Organisation King's College London 
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 04/2016
 
Description MRC Clinical Training Fellowship for Dr Hannah Burton
Amount £244,237 (GBP)
Funding ID MR/M01813X/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2015 
End 08/2018
 
Description MRC project Grant (Co-applicant with G. Lombardi)
Amount £483,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2013 
End 01/2016
 
Description Phenotype of B cells in patients with Chronic antibody-mediated rejection (Novartis Unrestricted Educational Grant)
Amount £49,997 (GBP)
Organisation Novartis 
Sector Private
Country Global
Start 06/2011 
End 12/2011
 
Description Preventing atherosclerosis by promoting endothelial cell regeneration through anticoagulant expression by smooth muscle progenitors
Amount £86,000 (GBP)
Funding ID PG/11/21/28797 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Pathfinder Award
Amount £147,307 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2018
 
Description Wellcome Trust Translation Award (Co-applicant with Richard Smith)
Amount £1,300,000 (GBP)
Funding ID 098300/Z/12/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2012 
End 12/2015
 
Description Lecture tour of China 
Organisation Xi'an Jiaotong University
Department School of Medicine Xi'an Jiaotong
Country China 
Sector Academic/University 
PI Contribution Lecturing to establish collaborations in research
Collaborator Contribution will be mutual cooperation on various projects
Impact None yet
Start Year 2013
 
Description Lecture tour of China 2 
Organisation Zhejiang University
Department Institute of Respiratory Medicine
Country China 
Sector Academic/University 
PI Contribution Hoping to gain collaborative partners in research
Collaborator Contribution Mutual cooperation in research projects
Impact none yet
Start Year 2013
 
Description MRC Centre for Transplantation 
Organisation King's College London
Department MRC Centre for Transplantation
Country United Kingdom 
Sector Public 
PI Contribution Team has become emerged within the centre
Collaborator Contribution Increased collaboration with Richard Smith, Steve Sacks, Gio Lombardi and Maria Hernandez-Fuentes. All have had significant intellectual input into the work
Impact Being within the MRC Centre, within King's College London, within Guy's Hospital has significantly contributed to success in applications to British Heart Foundation, Kidney Research UK and commercial organisations for research funding.
Start Year 2009
 
Description Mark Thursz 
Organisation Imperial College Healthcare NHS Trust
Department Liver Department
Country United Kingdom 
Sector Hospitals 
PI Contribution supply of mice. delivery of a seminar, plus intellectual input into the
Collaborator Contribution began a new line of enquiry in a model of liver fibrosis, looking at the contribution of coagulation proteins
Impact Abstract at international meeting 2012
Start Year 2010
 
Description Novartis 
Organisation Novartis
Department Transplantation & Immunology
Country Switzerland 
Sector Private 
PI Contribution Two way sharing of data and techniques - including a trip to Basel in August 2011 to visit Novartis Global Research and to give a talk
Collaborator Contribution Financial assistance, technical help
Impact Paper in preparation.
Start Year 2011
 
Description University of Michigan, Flint 
Organisation University of Michigan
Department University of Michigan-Flint
Country United States 
Sector Academic/University 
PI Contribution Provided a small laboratory project for biology students to come across to UK in last two summers and spend 4-6 weeks in my lab
Collaborator Contribution University of Flint have provided the students with all their living expenses
Impact Contributions to paper published in 2013 - PMID 23516969
Start Year 2011
 
Description Xi'an Jiaotong University, China 
Organisation Xi'an Jiaotong University
Country China 
Sector Academic/University 
PI Contribution Cooperation on a research project which has involved a senior post-doctoral scientist visiting China for 8 weeks
Collaborator Contribution They will provide the animals and team to assist in performance of experiments
Impact Awarded a King's Worldwide Partnership Fund Award to assist with the collaboration
Start Year 2013
 
Title Novel Antithrombotic Compounds 
Description Novel cell-tethered anticoagulants that were based in principle on the genetic tethering that we used in our early experiments 
IP Reference WO2011027175 
Protection Patent application published
Year Protection Granted 2011
Licensed No
Impact Has been used to secure Wellcome Trust money to take these compounds through clinical development
 
Title Thrombalexin 
Description membrane tethered hirulog, developed directly because of our work with the hirudin-trangenic mice. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2012
Development Status Under active development/distribution
Impact none yet 
 
Description KPA visit to MRC Centre labs 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact I organised an Open day for the MRC Centre for Transplantation attended by 60 patients. Two members of my laboratory presented the findings of the MRC-funded work to groups of patients throughout the mrning

increased interest in research by patients
Year(s) Of Engagement Activity 2011
 
Description Profiled in 'Open Heart' blog 
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 Professional Practitioners
Results and Impact Hoepfully encouraged more people to read the article

I am not aware of any impact yet,
Year(s) Of Engagement Activity 2015
URL http://openheart.circulationjournal.org/2015/04/anthony-dorling-phd.html
 
Description Talk to KPA, Guy's Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Lunchtime meeting attended by 50 or so patients, where I talked about my research, including that funded by MRC. Followed by questins and answer session

Increased interest in research by patients
Year(s) Of Engagement Activity 2010