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 mouse immune system can be made to tolerate transplants without long-term immunosuppressive drugs. The main emphasis will be to characterise a special set of lymphocytes (regulatory T cells) that act to prevent transplant rejection and to establish ways by which they can be selectively primed by the graft. We will use transgenic mice that express a uniform receptor committed to just one transplantation antigen, so eliminating the ?noise? from the vast majority of irrelevant lymphocytes from the analysis. These mice, and T cell clones and lines derived from them, will be used to follow the cell biology and key signalling mechanisms of these regulatory T cells. This information should lead to improved strategies to achieve tolerance in clinical transplantation, and to re-establish it in autoimmune disease.

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://www.molbiol.ox.ac.uk/pathology/tig/welcome.html that lays out our research activities.

Technical Summary

We have discovered that short courses of CD4 antibody therapy can enable tolerance to foreign proteins, transplanted tissues, and can restore tolerance in autoimmunity. In the absence of blood chimerism, transplantation tolerance requires the induction and participation of CD4+ regulatory T cells. This programme seeks to fulfil a number of objectives.
1) To evolve improved antibody-based strategies for induction of transplantation tolerance directed to the organ itself, and to the combination of organ and marrow stem cells.
2) To identify critical molecules that enable dendritic cells to tolerise T cells and polarise them towards regulatory function.
3) To identify the mechanisms by which regulatory T cells can suppress graft rejection.
We will exploit a number of resources that have already been established in this laboratory including TCR transgenic (A1.RAG-/-) mice whose CD4+ T cells have specificity for a single minor transplantation antigen - the male peptide Dby; technology for differentiating genetically transduced ES cells to become immature and matured dendritic cells; and a large database of SAGE libraries to provide a baseline for assigning relationships between cells and for identifying genes that are differentially expressed between cell populations.
The TCR transgenic mice will provide populations of monospecific T cells subjected to tolerising protocols within the TCR transgenic host, or within mice with a normal replete immune system, or in vitro. We will investigate the cell and molecular requirements of the inductive and effector processes exploited by regulatory T cells, and how these are integrated into the immune system as a whole.
This information should lead to improved strategies to achieve tolerance in clinical transplantation, and to re-establish it in autoimmune disease.

Publications

10 25 50

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CAMMS223 Trial Investigators (2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. in The New England journal of medicine

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

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Cobbold SP (2009) Infectious tolerance via the consumption of essential amino acids and mTOR signaling. in Proceedings of the National Academy of Sciences of the United States of America

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Daley SR (2008) Fc-disabled anti-mouse CD40L antibodies retain efficacy in promoting transplantation tolerance. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

 
Description therapeutic antibodies
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact application of immunology to treatment
 
Description Framework 7 Beta cell Therapy
Amount £300,000 (GBP)
Funding ID 241883 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2010 
End 12/2014
 
Title A strain of mouse to track regulatory T-cells 
Description A human cDNA encoding a humanmarker (CD2) was knocked into the mouse FoxP3 locus. Any regulatory T-cellexpressing FoxP3 can be identified by expression of CD2 on ghe cell membrane 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2008 
Provided To Others? Yes  
Impact Anew way to ablate regulatory T-cells in-vivo. Will greatly aid research in this field. 
 
Title SAGEgene database 
Description We used Serial analysis of Gene expression tofollow genes expressed in defined cell types.We have made that database public. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Hard to evaluate this. 
 
Title anti-IL7R 
Description antibodies to human IL7R for possible therapeutic development 
Type Of Material Antibody 
Provided To Others? No  
Impact awaiting commercial interest 
 
Title antibodies to PDL1, CD73, LAG3, CD103 
Description Monoclonal antibodies 
Type Of Material Antibody 
Year Produced 2010 
Provided To Others? Yes  
Impact enhance research activities of other groups 
 
Title knockout mice for b-cat1, GITRL, and CD73 
Description mice lacking these genes for study of function 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2009 
Provided To Others? Yes  
Impact use of these mouse models to study metabolic influences on immune regulation 
 
Title monoclonal antibodies to GITR and GITRL 
Description new monoclonal antibodies to defined subpopulations of white cells. 
Type Of Material Antibody 
Year Produced 2006 
Provided To Others? Yes  
Impact Catalysed research 
 
Description A novel treatment for relapsing-remitting multiple sclerosis 
Organisation University of Cambridge
Department School of Clinical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We developed and manufactured the therapeutic antibody used. We have supplied it to Prof A Compston since 1991, and with him and his colleagues evolved the protocols for treatment.
Collaborator Contribution We have been evaluating our antibody CAMPATH-1H in multiple sclerosis with this group since 1991. With antibody we manufactured in Oxford. CAMPATH1H has a long lasting beneficial effect in relapsing-remitting disease.A recent collaboration shows that the immunogenicity of the therapeutic antibody can be further reduced by pretolersing patients wit a non-cell-binding muitant of CAMPATH-1H
Impact Genzyme is now conducting Phase III studies, and there is every chance that this will become a licensed drug for multiple sclerosis. 16044212
 
Description Academic Phase II trial in human type I diabetes 
Organisation Free University of Brussels
Country Belgium 
Sector Academic/University 
PI Contribution We engineered the anti-CD3 antibody, manufactured it and di a great deal of preclinical testing and safety testing in the 1990s. The European consortium performed the clinical trial under the leadership of Prof Lucienne Chatenoud and Prof Daniel Pipeleers.
Collaborator Contribution We have shown that short term therapy can give long-term reversal of Type I diabetes, validating many of the concepts that started with our work on using antibodies to induce tolerance in the mid-1980s.
Impact Phase III trials are now in progress by Tolerx and GSK using our antibody but with modified prot0cols. our work was published in the New England Journal. 15972866
 
Description Crystal structure of the mouse GITRL 
Organisation University of Pennsylvania
Country United States 
Sector Academic/University 
PI Contribution We cloned and expressed the gene, Prof Mark Greene purified the protein and did the crystallograpphy
Collaborator Contribution Has suggested possible ways GITRL may bind to its receptor, and making some predictions of different biological outcomes
Impact PNAS publication. 18178614
 
Description GITRL antibodies as therapeutics for Type I diabetes 
Organisation Necker-Enfants Malades Hospital
Country France 
Sector Hospitals 
PI Contribution We made the anti-GITRL antibodies used in this study, and conceived the idea that they may be useful therapeutics.
Collaborator Contribution We made rat monoclonal antibodies to GITRL, and conceived the idea of using them as short term therapeutics to reverse autoimmune diabetes. We collaborated with Lucienne Chatenoud an expert in murine diabetes, and showed that anti-GITR antibodies exacerbate, while anti-GITRL antibodies reverse disease.
Impact PLOS publication. 19936238
Start Year 2006
 
Description creation of a reporter mouse for tracking regulatory T-cells 
Organisation RIKEN
Country Japan 
Sector Private 
PI Contribution I had the concept,and created the gene construct. Shohei Hori had the knock-in mouse made in the transgenic facility at the Riken
Collaborator Contribution This collaboration has enabled us to track and ablate regulatory T-cells in-vivo,opening up many hitherto refractory avenues of research.
Impact 16304635
 
Title 6120766 CDW52-specific antibody for treatment of multiple sclerosis 
Description short-term treatment benefits multiple sclerosis 
IP Reference US2005118172 
Protection Patent application published
Year Protection Granted
Licensed Yes
Impact Successful Phase III study . Will be sold as Lemtrada. Predicted to be most efficacious treatment for MS
 
Title Altered antibodies and their preparation 
Description A novel way to eliminate antibody immunogenicity and treatment side-effects 
IP Reference US6767996 
Protection Patent application published
Year Protection Granted
Licensed No
Impact n/a
 
Title Anti-CD4 antibodies 
Description Humanised anti-human CD4 antibody for therapy 
IP Reference US7541443 
Protection Patent application published
Year Protection Granted 2009
Licensed Yes
Impact n/a
 
Title Antibodies to the antigen Campath-1 
Description protection of antibodies to CD52 
IP Reference US6569430 
Protection Patent application published
Year Protection Granted
Licensed Yes
Impact part of poatent package for Alemtuzumab/Lemtrada-a licensed drug
 
Title Compositions and methods of tolerizing a primate to an antigen 
Description short term use of CD4 antibody to tolerise the immune system to foreign proteins 
IP Reference WO2004067554 
Protection Patent application published
Year Protection Granted
Licensed Yes
Impact Yes-fundamental discoveries on how the immune system regulates itself.
 
Title Humanized anti-CD3 specific antibodies 
Description Hmanisation serquence of therapeutic anti-CD3 antibody 
IP Reference US2007092516 
Protection Patent application published
Year Protection Granted 2007
Licensed Yes
Impact In trials
 
Title Methods of treatment using anti-CD3 antibodies 
Description CD3 antibodies as short term treatments for inflammatory arthritides (such as rheumatoid arthritis) 
IP Reference US7993641 
Protection Patent application published
Year Protection Granted 2011
Licensed Yes
Impact Trials have been accomplished in Type I diabetes but wrong doses chosen by GSK. Future trials in planning
 
Title Therapeutic antibodies 
Description Engineered antibodies to reduce immunogenicity 
IP Reference WO2010023482 
Protection Patent application published
Year Protection Granted 2008
Licensed No
Impact n/a
 
Title Otelixizumab (anti-CD3) 
Description anti-CD3 therapy for Type I diabetes. A non-lytic antibody that interrupts development of islet cell destruction, and given as a short term treatment preserves some islet cell mass long term.Should minimize long-term complications and management of diabetes 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2008
Development Status Under active development/distribution
Impact This is an example of a tolerising therapy that can reprogramme the immune system for therapeutic benefit. here fulfilling an unmet medical need. 
 
Description Murray Society,Lincoln college alumni 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Primary Audience Media (as a channel to the public)
Results and Impact Mostly--describing our short term therapies for long-term benefit to the media.

Tolerance is becoming a much more "popular" target for therapeutic strategies.I am sure we have had an influence.
Year(s) Of Engagement Activity 2006,2007,2008,2009