Research Objectives and Advanced Research Strategies
Research mission and themes
TRIG's Research Mission is:
To conduct high quality, relevant, novel and internationally competitive research in immunology, transplantation and regenerative medicine
To train and support future research and clinical leaders in immunology and transplantation
Some of our current research themes include:
- Visualising rejection and graft acceptance
- Understanding the impact of infection and memory T cells on transplant outcome
- Immunological profiling of leucocyte populations following transplantation
- Identification of therapeutic protocols that promote the development of regulatory T cells
- Understanding the role of B cells and other regulatory immune cells in transplantation tolerance
- Investigating the impact of immunosuppressive drugs on the development of cancer in transplant patients
- Discovering novel therapeutic interventions
- The interaction between stem cell derived tissues and the immune system
Advanced Research Strategies
Researchers in TRIG have the opportunity, experience, skills and facilities to conduct research which is at the forefront of basic, translational and clinical science.
Our research projects focus on key methodologies and techniques with the objective of delivering a more satisfactory outcome for people who undergo organ transplantation.
Our advanced research strategies include:
Biomarkers and Personalised Medicine
The development of Biological Markers* (Biomarkers) will benefit patients by allowing individualised patient treatment, i.e. tailor made therapy or personalised medicine. This means that clinicians will be able to reduce drug side effects and improve the quality of life for patients as the treatment they receive will be unique to their own specific needs.
Using this approach means that some patients may be able to benefit from reduced immunosuppression if they are shown to be at a lesser risk of rejection. It will also allow the clinician to make better decisions about the status of the patient’s health.
Our research has led to better tools for monitoring the immune status of transplant patients allowing their doctor to identify problems before they happen.
TRIG researchers are investigating potential biomarkers that will allow for:
• the analysis of a patient’s immunological pre-transplant status allowing them to receive an optimised combination of immunosuppressive drugs
• the early identification of rejection graft deterioration occurs
• the early demonstration of unresponsiveness or tolerance to the transplant
Working with transplant clinicians both locally and in Europe, we have tracked the immune system of transplant recipients to chart their immune status and reconstitution after treatment. This has contributed to the identification of valuable biomarkers which we are now going to use to identify patients at increased or reduced risk of rejection or of losing their transplant (See The BART Study and the RISET Final Report for more information).
Our recent involvement in the RISET project, of which Professor Kathryn Wood was the Scientific Co-Ordinator, (www.risetfp6.org) has meant that Biomarker tests to develop novel diagnostics which identify patients for whom immunosuppressive treatments could be safely minimized or withdrawn have been developed. The objective of our new studies is to validate these biomarkers in other transplant recipients to determine the feasibility of using them to guide multicentre clinical trials in transplantation. Some tests are now ready for commercial development in collaboration with industry. This will allow for broad access to the RISET tests by transplant centres throughout Europe as well as internationally and it is hoped that, eventually, this translational research will result in personalised medicine for transplant recipients.
New research being undertaken by the European BIOdrIM consortium (initiated Oct 2012), of which we are a member, is building on the results of RISET, by using decision making, based on validated biomarkers, to personalise immunosuppression for transplant patients. In this study, patients will be stratified according to their immunological responsiveness to their transplant with the aim of minimizing long term immunosuppression as much as is feasible and as early as possible in a bid to decrease the adverse effects of the immunosuppressive regimen.
*(A biomarker is something in the body that can be measured in order to tell doctors how a treatment is working or how a disease is progressing )
In order to maximise research potential it is no longer enough to conduct research in isolation; there is a need to produce results which can be translated into functional treatment which benefits the patient - “from bench to bedside”.
The TRIG research programme is designed to allow results from the laboratory to be taken as quickly and efficiently as possible into clinical practice leading to outcomes which will directly benefit the patient.
Our many and varied multi-disciplinary collaborations, locally and internationally, including those with industry and pharma companies, and our participation in projects which include clinical trials (including the RISET project, The ONE Study, OPTISTEM, the TRIAD study and BIODRIM) mean that the group can lead and participate in research which has meaningful results.
For example, our work on the TRIAD study (Tolerance Restoration in Autoimmune Disease by Selective Manipulation of the CD28 Costimulatory Pathway) in which we are a partner, investigates new therapeutic approaches to autoimmune disease, which will then lead in to clinical trials in patients. (See Novel Therapeutics for further information on the project )
Stem Cells and Regenerative Medicine
Stem cell science and regenerative medicine is extremely promising as stem cells offer the possibility of a renewable source of replacement cells and tissues, which will help to alleviate the pressure on donated organs. (Image below courtesy of Dr Karen English)
Regenerative medicine has the potential to increase the pool of donated organs for transplant purposes by aiming to regenerate in vivo or ex vivo human cells, tissues and organs in order to restore or establish normal function.
When you consider the statistics about the number of transplants carried out as opposed to those which are required, it is easy to understand how both stem cell science and regenerative medicine may make significant contributions to this issue in the future.
According to the NHSBT website (Nov 2012)
• More than 7,500 people currently need an organ transplant in the UK. • In 2011 - 12: 3960 people’s lives were transformed by a transplant • BUT - About 1,000 people die every year in the UK while waiting for an organ transplant or because they become too ill to survive an operation and are removed from the list.
In TRIG, we are currently conducting research using two different types of stem cell
- Mesenchymal stroma cells (MSCs) which are adult stem cells, and
- Induced pluripotent stem cells (iPSCs) which are stem cells that have been manipulated to produce a certain type of cell.
Some of the research that we have been involved in is for new treatment protocols which are under investigation in clinical trials. These may provide an advanced cell therapy approach which would allow a patient at risk of blood cancer to rapidly reconstitute their immune system after a stem cell transfusion. This may mean that high risk patients are likely to remain free of the disease and have reduced chances of other infections, allowing them to remain healthy without immunosuppression.
B Cells as a therapeutic agent
We are currently investigating B cell tolerance, and B cell function, to determine how these specialised immune regulatory cells may control or suppress the immune response against a transpalnt. B cells that have the ability to secrete IL-20 have been shown to have regulatory properties and are an exciting and newly discovered cell type that have roles in various autoimmune and inflammatory diseases.
The role of B10 cells in transplantation tolerance has yet to be uncovered. Our research is aimed at elucidating the role these cells play in acceptance of transplanted tissues and investigating ways to use these cells as therapeutics to promote long term graft survival.
The TRIAD Project (Tolerance Restoration in Autoimmune Disease by Selective Manipulation of the CD28 Costimulatory Pathway) provides an innovative strategy to autoimmune diseases therapy, which is based on an antibody approach with a well established mechanism of action. During the study, the partners will:
- investigate the efficacy of a new selective antagonist of CD28,
- confirm the mechanisms of action and
- evaluate the potential of its immune toxicity
The concept is based on suppressing only the parts of the immune system responsible for the autoimmune attack, rather than suppressing the immune system as a whole, while sparing and enhancing regulatory T cells. It is envisaged that the end result will be a novel therapeutic agent which will then be used in phase I and phase II clinical trials in patients.
In vivo and in vitro monitoring and visualisation of cells
We are using new and emerging techniques such as confocal and multiphoton microscopy to develop our understanding of the mechanisms of tolerance and rejection. It is established that regulatory T cell presence within the allograft is important for control of rejection. However, our understanding of where Treg are acting to exert this control is limited. Using multi-photon microscopy will allow us to observe regulatory T cell interactions within the allograft.
Data Management and Data Repositories
The TRIG BART database and RISET database
In order to maximise the research results and, in some cases, the related clinical data, TRIG has developed and has access to several valuable data resources.
TRIG BART database
The BART study - BIOMARKER ANALYSIS TO DETECT REJECTION AFTER KIDNEY, PANCREAS OR KIDNEY/PANCREAS TRANSPLANT - is a study to evaluate whether the sequential analysis of the phenotype and functional status of memory T cells and the presence of donor reactive antibodies in the peripheral blood or urine of kidney, kidney/pancreas recipients will provide sensitive and specific biomarkers that enable the onset of graft rejection to be predicted and treated before the transplant sustains any injury.
TRIG* researchers, namely Sebastiaan Heidt and Sushma Shankar have devised and refined a database which contains all the relevant sample and clinical data for the patients enrolled on the study. The database has been reviewed by the BART study group to ensure it captures all of the required information in the most appropriate way. This will enable reporting and analysis of research data together with clinical events and will allow the researchers to see and understand a unilateral picture of a patient’s progress from pre transplant to up to five years afterwards. The database will provide comprehensive information about the samples which are stored, demographic information about the transplant recipients and information about living donors. The biobank being developed is a valuable resource for the research group.
*With thanks to Rajeev Kumar from Prof Freddie Hamdy’s group who built the database application.
As part of the RISET study a data repository was built which stores the clinical data and immunomonitoring results obtained with the tests. This Data Repository is a unique resource on the follow-up of patients in tolerance investigation studies. A longitudinal visualization tool, the LifeLines program allows representation of both clinical and experimental data in a unified way and allows investigation of the relationship between clinical events and test results in order to support the validation of biomarkers. Members of TRIG have access to the database as part of their involvement in the RISET project.