Characterisation of the phenotypic and functional characteristics of CD25+ regulatory T cells in vivo.

Lead Research Organisation: University of Wales
Department Name: UNLISTED

Abstract

Our immune systems recognise infectious agents responding in a variety of ways resulting in eradication of the particular pathogen involved. Whilst ridding the body of infectious agents, the immune system must not destroy healthy tissue ( a process termed autoimmunity). In the majority of cases the immune system is able to discriminate between infected and healthy tissue, however, 3 - 5 % of the general population suffer from autoimmune diseases e.g. multiple sclerosis and type I diabetes, indicating that under certain circumstances control mechanisms within the immune system do break down. On the other hand, cancer cells are normally not attacked by the immune system since these cells resemble healthy and not infected tissue. Thus in this situation it would be beneficial to be able to manipulate the immune system in a way which would override normal control mechanisms thereby allowing destruction of the tumour cells. The aim of this research is to gain an understanding of pathways, which control how the immune system perceives what is healthy and what is harmful. Such an understanding is an essential pre-requisite for the design of strategies aimed at treating individuals suffering from either autoimmune disease or cancer.

Technical Summary

The overall aim of this project is to understand how the immune system is able to discriminate between healthy tissue and infected tissue. The importance of this aim stems from the fact that when the ability to discriminate breaks down, attack of healthy tissue by the immune system can result in the development of autoimmune disease such as diabetes and arthritis. Conversely, cancer cells are normally not attacked by the immune system since these cells resemble healthy tissue and not infected tissue. Understanding ways in which the immune system discriminates between healthy and infected tissue is central to the design of therapeutic strategies aimed at treating both autoimmune disease and cancer. An accumulating body of evidence suggests that the function of a population of lymphocytes, named CD25+ regulatory cells, is to prevent the immune system from targeting healthy tissue. It has been shown, in animal models, that these cells inhibit the development of immune responses against cancer. Similarly, it has been shown that these cells can inhibit development of autoimmune disease. Many features of these cells are not well understood. This laboratory, based at the University of Wales College of Medicine, has established an experimental model whereby the impact of CD25+ regulatory T cells on both autoimmune disease and tumour immunity can be studied within the same experimental setting. This model will be used to determine the biological parameters, which govern the activity of CD25+ regulatory cells. The success of this project depends upon both national and international collaborations. Thus, collaborators include Dr Philippe Gasque at the University of Wales College of Medicine, Dr Simon Jones at the University of Cardiff, Dr Persephone Borrow at the Jenner Institute for Vaccine Research, Dr Annette Oxenius at the University of Zurich, Professor Hans-Joerg Schild at the University of Tuebingen and Dr Fiona Powrie at the University of Oxford. The clinical benefits of manipulating CD25+ regulatory cells are potentially very significant. Enhancing the activity of these cells may prevent autoimmunity whilst suppressing their activity may promote immunity to tumours. This projects aims to develop an understanding of how CD25+ regulatory cells work in order that their full potential as targets for immunotherapy can be realised.

Publications

10 25 50
 
Description MRC Research Grant
Amount £498,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2009 
End 04/2012
 
Description PhD Studentship
Amount £80,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description PhD Studentship
Amount £80,000 (GBP)
Organisation GW4 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 12/2019
 
Description Programme Grant
Amount £800,000 (GBP)
Organisation Cancer Research Wales 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 08/2021
 
Description Wellcome Trust Project Grant (CD59 as a modulator of T cell activity in vivo)
Amount £168,228 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2006 
End 02/2008
 
Description Wellcome Trust Project Grant (The Role of Interleukin-6 in Generation and Maintenance of Influenza-Specific CD4+ T Cell Memory)
Amount £247,075 (GBP)
Funding ID 080340 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2007 
End 05/2010
 
Description Wellcome Trust University Award (Identification of mechanisms underpinning regulatory T cell involvement in disease)
Amount £829,539 (GBP)
Funding ID 086983 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2009 
End 10/2015
 
Description Evaluating the Role of CD59 in Modulating CD4+ T cells 
Organisation Cardiff University
Department Infection and Immunity
Country United Kingdom 
Sector Academic/University 
PI Contribution Generated mouse models of virus infection to test role of CD59 in modulating T cell activity Provision of cohort of cancer patients and assays to test role of CD59 in modulating activity of human T cells
Collaborator Contribution Provision of mice, reagents and expertise
Impact Two papers in Journal of Immunology One paper in European Journal of Immunology Review in Trends in Immunology
 
Description Evaluating the Role of Regulatory T cells in Patients with Cancer 
Organisation Cardiff University
Department Infection and Immunity
Country United Kingdom 
Sector Academic/University 
PI Contribution Use of assays to perform phenotypic and functional characterisation of regulatory T cells in patients with cancer.
Collaborator Contribution Enabled our findings using animals models to be rapidly tested in patients with cancerExpertise in human immunology
Impact 17205133 PhD studentship from Cancer Research Wales Wellcome Trust University Award
 
Description Evaluating the Role of Regulatory T cells in Patients with Cancer 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution Use of assays to perform phenotypic and functional characterisation of regulatory T cells in patients with cancer.
Collaborator Contribution Enabled our findings using animals models to be rapidly tested in patients with cancerExpertise in human immunology
Impact 17205133 PhD studentship from Cancer Research Wales Wellcome Trust University Award
 
Description Role of CD62L in homing of anti-viral and anti-tumour T cells 
Organisation Cardiff University
Department Infection and Immunity
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of experimental model to study T cell homing
Collaborator Contribution Provision of mice and expertise to enable the study of T cell homing
Impact Publication in the Journal of Immunology
Start Year 2006
 
Title CLINICAL TRIAL - TACTICC 
Description The intervention was a pilot study to assess the effect of regulatory T cell depletion on 5T4-containing MVA (TROVAX®) vaccination in patients with inoperable metastatic colorectal cancer. In this randomised, open-label, phase 2 clinical trial, TaCTiCC (TroVax® and Cyclophosphamide Treatment in Colorectal Cancer), we recruited patients with inoperable, metastatic CRC, with prior stable or responding disease following 12 weeks standard chemotherapy. Patients were centrally randomised to receive either no treatment (watch & wait unless clinically indicated; Group 1), metronomic oral 50mg B.D. CPM on treatment weeks 1 & 3 (Group 2), intramuscular injections of 1x109 TCID50 TroVax® on treatment weeks 4, 6, 8, 10, 12 and 16 (Group 3), or a combination of the two treatments (Group 4). The primary endpoint was the magnitude of anti-5T4 immune responses generated at treatment week 7, as determined by the presence of 5T4-specific T cell responses by IFN-? ELISPOT and 5T4 antibodies by ELISA. Secondary endpoints included analysing the kinetics of anti-5T4 responses, progression-free survival (PFS) and overall survival (OS). This trial is registered with EudraCT (2010-024380-41) and the ISRCTN registry 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Initial development
Year Development Stage Completed 2016
Development Status Actively seeking support
Clinical Trial? Yes
Impact Prior depletion of Tregs by CPM does not boost immune responses generated to TroVax® vaccination, however, both CPM and TroVax® independently induced beneficial anti-tumour immune responses resulting in prolonged survival of end-stage CRC patients without toxicity. These data warrant further investigation of the two treatments in separate, larger clinical trials.Funding applications are underway. 
URL http://www.isrctn.com/ISRCTN54669986
 
Description Documentary for BBC World 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A film sponsored by the AICR was produced and televised on BBC World.

I have no information regarding its audience.
Year(s) Of Engagement Activity 2006