Therapeutic Immunoregulation.

Lead Research Organisation: University of Oxford
Department Name: Sir William Dunn Sch of Pathology

Abstract

We will establish the rules by which the immune system can be encouraged to take control and reverse immune and inflammatory damage to body tissues. The main emphasis will be to characterise a special set of peacemaker lymphocytes (regulatory T cells) that have the capacity to curb inflammation. By understanding how these cells function we will be in a better position to exploit them, or even to bypass them, with new forms of targeted medication. This information should lead to improved strategies to harness natural regulatory mechanisms to control unwanted inflammatory and immune damage We have exhibited at Royal Society soirees and exhibitions, and have given lay lectures on ?reprogramming? and therapeutic antibodies to the Royal Institution and to school parties visiting Oxford. We maintain an active website http://users.path.ox.ac.uk/~scobbold/tig/welcome.html that lays out our research activities.

Technical Summary

We discovered, in mice, that short courses of therapy with certain antibodies directed against T-cells could give long-term tolerance to foreign proteins and transplanted tissues, and could restore tolerance in autoimmunity. We have shown that short-term anti-T-cell therapy can also have long-term clinical benefits in multiple sclerosis and in Type I diabetes. The proper harnessing of this ?reprogramming? for clinical application requires that we should understand its mechanisms. Mouse models have taught us that, in most cases, tolerance requires the activity of CD4+ regulatory T-cells (Treg) that provide collateral protection to many antigens in the same tissue, and a role for the cytokine TGFbeta. Our capacity to understand how and when Treg operate has been constrained by the lack of a clear targetable cell surface marker. This we have now circumvented by creating a knock-in mouse with a human CD2/CD52 chimeric construct expressed under the control of the Foxp3 gene. In this way all Foxp3-expressing cells can now be identified or ablated with antibodies. Our derivation of a T-cell leukaemia line which can be easily induced to expresss Foxp3, provides a resource to investigate signalling pathways leading to the induction of Foxp3. In this program we hope to: 1) Use our ablative approaches to establish if and when Foxp3+ Treg act in the induction and maintenance of tolerance, linked suppression, and infectious tolerance; 2) Extend our recent discoveries that Treg and TGFbeta turn on cascades of enzymes concerned with catabolism of essential amino acids, and the generation of adenosine and, in conjunction with effects on the mTOR pathway, convert other T-cells to regulatory function. 3) Interrogate the role of the tissue microenvironment in promoting the function and further generation of Treg. 4) Utilise this information to develop improved strategies to harness regulatory mechanisms to control unwanted inflammatory and immune damage.

Publications

10 25 50
publication icon
Agorogiannis EI (2012) Th17 cells induce a distinct graft rejection response that does not require IL-17A. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

publication icon
Chatenoud L (2012) CD3 monoclonal antibodies: a first step towards operational immune tolerance in the clinic. in The review of diabetic studies : RDS

publication icon
Cobbold S (2013) Regulatory Cells and Transplantation Tolerance in Cold Spring Harbor Perspectives in Medicine

publication icon
Cobbold SP (2011) Biomarkers of transplantation tolerance: more hopeful than helpful? in Frontiers in immunology

publication icon
Farquhar CA (2010) Tolerogenicity is not an absolute property of a dendritic cell. in European journal of immunology

publication icon
Greene MI (2010) Regulation of the immune response. in Current opinion in immunology

 
Title a transgenic mouse for tracking regulatory T-cells 
Description a mouse expressing human CD2 on its regulatory T-cells, so permitting tracking, isolation and ablation of this cell type for research 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2010 
Provided To Others? Yes  
Impact a new opportunity to study a cell type with huge therapeutic implications 
 
Description role of TGfb in immunological tolerance 
Organisation Sanofi
Department Genzyme Corporation
Country United States 
Sector Private 
PI Contribution readout assays
Collaborator Contribution provision of reagents
Impact identified new roles for TGFb in evoking adenosine generation
Start Year 2010
 
Description the construction of a novel reporter mouse for FoxP3 expression - Dr Shohei Hori 
Organisation RIKEN
Country Japan 
Sector Private 
PI Contribution Creation of the reporter construct
Collaborator Contribution creation of a useful nmouse strain ck and ablate regulatoy T-cells
Impact The kendal paper in J. Exp.medicine this year (2011)
Start Year 2006