Overcoming immunological barriers to regenerative medicine

Lead Research Organisation: King's College London
Department Name: Genetics and Molecular Medicine

Abstract

The goal of the field of regenerative medicine is to replace damaged or diseased tissue and thereby find cures for diseases that are currently untreatable. At present two different approaches appear feasible: one is to stimulate the body's own cells to repair the tissue and the other is to transplant new cells into the body. In the case of cell transplantation one could transplant cells from one individual to another (allogeneic cells), as happens routinely in blood donation. Alternatively, one could isolate a small number of a patient's own skin or blood cells and convert them in the lab into cells called pluripotent stem cells that can then form any tissue in the body, so that patients can be treated with their own cells.

No matter which strategy is taken, it is essential to overcome the body's natural immune defences in order for the treatment to succeed. In the case of allogeneic cells, the body recognises that the cells as foreign and kills them - the reason why this is not a problem in blood donation is that there are so many donors in the population that good matches for different individuals can be found. Even when the potential treatment involves the patient's own cells, the immune system can be provoked in response to tissue damage, resulting in inflammation whereby immune cells of the body respond to danger signals and engulf the transplanted cells.

We have assembled a team of researchers from different backgrounds to collaborate in order to find new ways to control the immune system to make regenerative medicine treatments more effective. Our team includes researchers with many years' experience in organ transplantation, who are developing ways of reducing the need for immunosuppressive drugs, and researchers who are already carrying out clinical trials of cell transplantation to cure certain forms of blindness and liver failure. We also have experts who are comparing whether cell transplantation or endogenous repair are better approaches for treating heart failure, experts in immunology, pluripotent stem cells and cells from adult tissues.

We have set out to answer three questions that are of central importance in regenerative medicine. We want to identify the proteins that transplanted cells secrete to communicate with the immune system and discover whether different cell types produce different signals. It might be that liver cells produce different signals to eye cells, or that liver cells produce different signals if they have come from an adult rather than a pluripotent stem cell. This information will help us decide whether cells from one source might be better for transplantation than those from another source, and will also give us clues about the best ways to protect the cells from immune attack. The next question is whether the signals we identify as potentially contributing to transplant failure can be blocked, for example by coating cells with a protein that protects them from attack or by transplanting back immune cells generated from pluripotent stem cells. The final question is how inflammation contributes to endogenous repair and influences the fate of transplanted cells. We will identify different types of inflammatory cell and then examine whether destroying each cell type improves or worsens tissue repair.

Our research will lead eventually to improved treatments for blindness, heart failure, liver failure and inflammatory bowel disease. Our discoveries will be shared with other researchers, so that they can apply our observations, experimental skills and tools to other important diseases. We believe that collaborations amongst researchers with very different perspectives offer the best opportunity to harness the body's immune system to make treatments more effective.

Technical Summary

The innate and adaptive immune system can present formidable obstacles to successful regenerative medicine applications. To identify and circumvent these obstacles, the co-applicants propose to form a UK Regenerative Medicine Platform (UKRMP) hub on immunomodulation. We will pool our collective clinical and laboratory-based expertise in stem cell biology, whole organ transplantation, cell therapy, endogenous tissue repair and innate and adaptive immunity to answer the following questions:

1. How do differentiated cells signal to the host innate and adaptive immune system?
2. How do transplanted cells provoke adaptive immune responses?
3. How does the inflammatory niche contribute to endogenous repair and influence the fate of transplanted cells?

Each question will be tackled in one work package. In work package 1 we will use in vitro assays to compare how differentiated human cells isolated from the relevant tissue or induced from iPS cells signal to the immune system under steady state and hypoxic conditions. In work package 2 key findings from work package 1 will be validated in vivo using humanised mice. The use of iPS cell-derived dendritic cells to modulate immune tolerance and enhance Treg therapy, alone or in combination with complement inhibitory peptides, will be explored as a means of improving the survival and function of transplanted cells. In work package 3 we will examine the contribution of recently discovered subsets of macrophages, fibroblasts and dendritic cells to the inflammatory niche in the context of cell transplantation, chronic inflammation and endogenous repair.

Each question will be approached in the context of the following long-term clinical deliverables: improved efficacy of photoreceptor cell therapy to treat blindness; improved repair of damaged heart and intestine; and improved survival and functionality of transplanted hepatocytes as an alternative to liver transplantation.

Planned Impact

WHO WILL BENEFIT FROM THIS RESEARCH?
The immediate academic beneficiaries include all investigators who participate in the immunomodulation hub, both as PIs and collaborators, and all investigators associated with the UK Regenerative Medicine Platform. The benefit will extend to the diverse stem cell biology, transplant, immunology and cancer research communities in the UK and internationally. Clinicians involved in organ transplantation and regenerative medicine therapies will also be beneficiaries. The commercial sector will benefit, including companies named in the application, companies who subsequently partner the hub and companies that are less directly associated with the area. Members of the lay public, both healthy individuals and patients, will benefit. UK government agencies, including politicians, the Technology Strategy Board (TSB), MRC and regulatory agencies, such as the MHRA, will benefit. The benefits will not be restricted to the UK but will have an impact globally.

HOW WILL THEY BENEFIT FROM THIS RESEARCH?
Academics will benefit by increased knowledge of how the immune system can be harnessed to improve regenerative medicine therapies, through obtaining data to facilitate further funding applications and publications, through career progression and, particularly in the case of the staff employed directly on the grant, training opportunities that enable them to pursue an independent research career or transfer to other employment sectors (timescale: 3-5 years).

Several of the PIs involved in this application are clinically active and have close associations with NIHR Biomedical Research Centres. Clinicians will benefit by obtaining new knowledge that leads to the design of new clinical trials (timescale: 3-8 years).

Patients will benefit by improved treatment for a variety of diseases that currently lack optimal treatments, including heart failure, inflammatory bowel disease, blindness, and liver failure (time scale: 5-15 years). Healthy individuals will benefit by improved quality of life in old age (timescale 10-15 years), increased understanding of research (timescale 3 years), increased willingness to participate in clinical trials (timescale 3-5 years), and by seeing the successful achievement of key goals within the charitable sector, such as the British Heart Foundation (timescale: 5-10 years).

The commercial sector will benefit by having new knowledge on which to develop new therapeutics, new possibilities for partnering with academics, facilitated by the TSB Cell Therapy Catapult, and by selling materials, such as kits and antibodies, to researchers funded by the hub (timescale: 1-10 years).

The UK government (timescale: 1-15 years) will benefit by generation of intellectual property, leverage of ongoing MRC investment in the Centre for Transplantation, commercialisation of products arising from the research, reduced health care costs and by involvement in the work force of people who would otherwise be unable to work through ill health. The reduced burden to the National Health Service will allow resources to be channelled into other areas, such as acute care. The stature of the UK internationally will increase, because the research carried out by the hub will impact on the global field of regenerative medicine.

Publications

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Alhabbab R (2018) Galectin-1 is required for the regulatory function of B cells. in Scientific reports

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Boardman DA (2017) Expression of a Chimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potency of Human Regulatory T Cells in Preventing Human Skin Transplant Rejection. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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Boardman DA (2016) What Is Direct Allorecognition? in Current transplantation reports

 
Description Crack It Mini Challenge : Monitoring contractility of bio-realistic human cardiac tissue in vitro
Amount £100,000 (GBP)
Funding ID NC/C013106/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2014 
End 07/2014
 
Description Demonstrating that Extracellular vesicles from iPSC-derived hepatocytes can positively modulate immunosuppression 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Determining immunosuppressive activity of extracellular vesicles both in vitro and in vivo
Collaborator Contribution Immunophenotyping of extracellular vesicles
Impact 1. Immunophenotyped extracellular vesicles from iPSC-derived hepatocytes 2. Extracellular vesicles with demonstrated immunosuppressive activity from iPS-derived hepatocytes.
Start Year 2016
 
Description Microparticles for the induction of immune tolerance in the transplant niche 
Organisation University of Nottingham
Department School of Mathematical Sciences Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Testing controlled PLGA microparticles for local induction of immune tolerance in two complementary transplantation models
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Impact 1. PLGA microparticles with varying release profiles, soluble factors, and presented tethered ligands 2. Microparticles for tolerance induction in a mouse skin graft model 3. Microparticles as an adjunct therapy to IPS delivery in a liver fibrosis model
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Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Transplanting hepatocytes (iPSC and adult) into a humanised mouse model of acute liver failure i
Collaborator Contribution Development of humanised mouse model of acute liver failure
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Form Of Engagement Activity A formal working group, expert panel or dialogue
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Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
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Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact The goal of the field of regenerative medicine is to replace damaged or diseased tissue and thereby find cures for diseases that are currently untreatable. At present, two different approaches appear feasible: one is to stimulate the body's own cells to repair the tissue; and the other is to transplant new cells into the body, but both approaches are classed cell therapies. The drive to move regenerative medicine from the bench to clinic is currently at its strongest and on an international scale, which has resulted in many opportunities and challenges for the field.

What viewers learn:
*The regulatory landscape in the UK
*The role of the commercial sector
*Logistics involved in clinical trials
*The future potential of cell-based therapies

Who this will interest:
*Basic researchers in regenerative medicine
*Clinicians involved in regenerative medicine clinical trials
*Regenerative medicine investors
Year(s) Of Engagement Activity 2015
URL https://www.youtube.com/watch?v=t56dUDlMjV0