Targeting the complement system in transplantation

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

Abstract

Complement consists of a normal set of circulating proteins whose role in fighting infection is long established, but which is also now known to impede the acceptance of healthy foreign tissue such as a kidney transplant. Complement seems to work together with more sophisticated elements of the immune response called T lymphocytes, and we now believe that collaboration between complement and T cells is essential for graft rejection. It follows that blocking the alliance between complement and lymphocytes may hold a key to a new method of treatment, which could lead to more effective prevention of graft rejection and allow lower use of toxic drugs that are directed against T lymphocytes. However in order to plan effectively, we need better understanding of the cells that produce and secrete complement and how complement enhances the performance of these cells to stimulate T lymphocytes. From a shortlist of two cell types transferred with the donor kidney, we propose to examine the relative importance of these cells types in triggering graft rejection. We also have strategies for reducing the secretion of complement by these cell types, and wish to see if we can build this into a treatment strategy suitable for clinical therapy. More effective ways to prevent rejection crises would be expected to cut graft losses in the short and long term, and thus lead to a significant health and economic benefit associated with transplant success.

Technical Summary

Our laboratory has been instrumental in defining the role of complement in renal transplant rejection, in particular the role of local production of C3 on the inflammatory and immune responses influencing short and long term transplant survival. Key publications in Nature Medicine and the NEJM describe our findings. In order to correctly target therapeutic regulators that form part of our translational programme, we need to precisely identify the cell types whose properties depend on this local production. Parenchymal tissue cells and migratory antigen presenting cells (APC) of donor origin are prime candidates, as both are known, from our work on isolated cells, to secrete C3 and stimulate the immune system in a complement dependent manner. However we need to establish the primacy of these cell types on a more physiological basis and determine whether cell-targeted inhibition of the complement system is relevant to the goal of inducing immune hyporesponsiveness for human therapy. To accomplish this we will work to the following set of objectives. (1) We will generate mouse chimeras which produce C3 in either parenchymal or passenger APCs. Transplantation of organs from these mice will tell us the extent to which the recipient antidonor T cell response is dependent on parenchymal or passenger cell synthesis of C3. (2) Functional studies on APCs from the chimeric mice will determine if their potency for T cell stimulation is dependent on endogenous or exogenous synthesis of C3. (3) We will build a therapeutic strategy for inactivating complement at the surface of parenchymal cells and/or APCs using a membrane targeted complement regulator in a mouse model. (4) We shall extend our findings to a human system based on either peripheral blood and myeloid APC, or renal parenchymal cells, and human T cells. Our aim will be to show if gene silencing, protein inactivation or receptor blockade of C3 reduces the human T cell response and favours the generation of inhibitory T cells. Further exploitation of human therapy would then require targeting the relevant cell type, with appropriate timing at the correct location.

Publications

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Farrar CA (2013) The innate immune system and transplantation. in Cold Spring Harbor perspectives in medicine

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Farrar CA (2014) Mechanisms of rejection: role of complement. in Current opinion in organ transplantation

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Farrar CA (2016) Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury. in The Journal of clinical investigation

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Hernandez-Fuentes MP (2018) Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

 
Description Technology Strategy Board Assessor Briefing for Healthcare
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description British Transplant Society Fellowship Award
Amount £40,000 (GBP)
Organisation British Transplantation Society (BTS) 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2008 
End 10/2009
 
Description MRC Centre Grant (Directors Initiative)
Amount £250,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2007 
End 09/2012
 
Description MRC Developmental Clinical Study
Amount £1,727,417 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2011 
End 06/2014
 
Description MRC Project Grant
Amount £600,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2008 
End 09/2011
 
Description MRC Public Engagement Grant
Amount £10,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2010 
End 10/2010
 
Description NIHR Senior Investigator award
Amount £40,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2008 
End 04/2012
 
Title Complement imaging technology 
Description Cloning of complement receptor 2 and modification to develop a new imaging tool for detection of complement activation by external body imaging. 
Type Of Material Technology assay or reagent 
Year Produced 2011 
Provided To Others? Yes  
Impact Imaging ligand adapted for potential clinical studies 
 
Description Complement and Coagulation interaction in hyperacute rejection 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Rat model of hyperacute rejection. Model for therapeutic intervention by treatement of the donor organ with membrane associated thrombin and complement regulators
Collaborator Contribution It has exposed new interactions between thrombin and complement regulators induced by antibody bidning and has identified a new therapeutic strategy for prevention of rejection
Impact Presentation of findings at international complement and transplant meetings. Potential new treatment strategy relevant to sentised transplant recipients. New IP registered for the membrane targeted antithrombin (PTL004 and PTL006).
Start Year 2008
 
Description Complement and Coagulation interaction in hyperacute rejection 
Organisation King's College London
Department MRC Centre for Transplantation
Country United Kingdom 
Sector Academic/University 
PI Contribution Rat model of hyperacute rejection. Model for therapeutic intervention by treatement of the donor organ with membrane associated thrombin and complement regulators
Collaborator Contribution It has exposed new interactions between thrombin and complement regulators induced by antibody bidning and has identified a new therapeutic strategy for prevention of rejection
Impact Presentation of findings at international complement and transplant meetings. Potential new treatment strategy relevant to sentised transplant recipients. New IP registered for the membrane targeted antithrombin (PTL004 and PTL006).
Start Year 2008
 
Description Requirement of complement C3 for transplant tolerance induction 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Led to the initial observation that C3 deficient mice were resistant to tolerance induction.
Collaborator Contribution Provided a Clinical Fellow with an interest in complement and transplantation. This has enabled a new scientific question to be addressed.
Impact The initial results showing the requirement for C3 in tolerance to skin grafts was presented at an international meeting.
Start Year 2008
 
Description The role of the lactin pathway (MASP2) in ischemia reperfusion injury 
Organisation University of Leicester
Department Department of Infection, Immunity and Inflammation
Country United Kingdom 
Sector Academic/University 
PI Contribution Models for ischemia reperfusion injury in native and transplant organs using knockout mice.
Collaborator Contribution Revised my thinking on the complement pathway responsible for triggering complement activation during and after transplantation
Impact Presentation at International complement and transplant meetings Publication in PNAS; second publication submitted Collaboration with industry (OMEROS) on a new theraputic monoclonal antibody
Start Year 2006
 
Title Membrane targeted anti-thrombin PTL006 
Description A membrane targeted anti-coagulant for intented use in donor kidneys transplanted into high risk (highly sensitised) recipients. Currently at proof-of-principle stage in rat model. Current funding - MRC Centre Grant Directors Initiative. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Patent application registered. 
 
Description BBC Radio 4 Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Prof Steven Sacks describes his work on finding an easier way to get the body to accept a new organ on BBC Radio 4.

Publicity for the MRC Centre for Transplantation.
Year(s) Of Engagement Activity 2008
 
Description BBC Radio 4 Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact BBC Radio 4 invited Professor Steven Sacks to talk about a new technique that would extend the life of a kidney transplant significantly.

The story received media attention and was later supported by the successful application of an award to help with first in man clinical trials.
Year(s) Of Engagement Activity 2010
 
Description ISN Nexus 2016 Berlin 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker and session chair ISN Nexus Symposium Berlin to share results and provoke discussion.
Year(s) Of Engagement Activity 2016
 
Description Kidney Patient's Association Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Primary Audience Participants in your research and patient groups
Results and Impact Laboratory visit and talk concerning ongoing research.

Articles in National KPA Newsletter
Year(s) Of Engagement Activity 2009
 
Description Seminar - Sir William Dunn School of Pathology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Interest and further discussions followed

Strengthened links in support of application for UKRMP Immunology Stem Cell Hub
Year(s) Of Engagement Activity 2014
 
Description Session Organiser for BSI 2013 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact None as yet - Meeting occurring 2-5 December 2013
Year(s) Of Engagement Activity 2013
URL http://www.bsicongress.com/