Therapeutic Immunoregulation.

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.

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.