A balanced immune response is maintained by a network of regulatory cells including T cells, B cells and iNKT cells. How these cells respond to their environment in order to dampen down inflammation and what goes wrong in autoimmunity, will be the focus of this meeting. Novel insights into positive and negative feedback mechanisms that help balance the immune environment will be discussed. It is only by understanding how immune regulation is maintained in health and what goes wrong during autoimmunity that new targets for therapy can be identified.
We welcome abstract submission for this meeting: selected abstracts will be selected for short oral presentation.
This event has CPD accreditation and will have a discussion panel session.
Meeting Chairs: Dr Elizabeth Jury , UCL, London, Professor Robert Barker, University of Aberdeen
On registration you will be able to submit your questions to the panel that will be asked by the chair on the day of the event
9:00 – 9:45 Registration
9:45 – 10:00 Introduction by the Chairs:
10:00 – 10:30 The induction of antigen-specific regulatory T cells for suppression of autoimmune disease
Professor David C Wraith, Professor of Experimental Pathology, Department of Cellular and Molecular Medicine, University of Bristol
This talk will compare and contrast different ways of inducing antigen-specific regulatory T cells. Effective control of autoimmunity may involve induction of foxp3 expressing cells or the generation of negative feedback mechanisms involving interleukin 10. Repetitive administration of soluble peptide induces peripheral tolerance. This is characterised by anergic, IL-10 secreting CD4+ T-cells with regulatory function. In a model of inflammatory autoimmune disease, IL-10 Treg cells retain the capacity to co-produce interferon gamma and concomitantly express T-bet, demonstrating their Th1 origin. IL-10 Treg cells suppress dendritic cell maturation, prevent Th1 cell differentiation and thereby create a negative feedback loop for Th1 driven immune pathology. Similar negative feedback loops for Th2 and Th17 driven pathologies will be described. The use of peptides for therapy of multiple sclerosis has been tested in a phase I/IIa clinical trial. The results of the trial will be discussed.
10:30 – 11:00 Imaging Immunity and Tolerance in vivo
Professor James Brewer, University of Glasgow¸ Scotland
Much of what we understand about the anatomy and architecture of the immune system was revealed through exquisite experiments performed in the 1950’s to 70’s. These studies identified the role that anatomy played in a number of fundamental immunological phenomena including recirculation, induction of immune priming or tolerance and the interactions of T and B cells. The recent resurgence of interest in the role of immune architecture and anatomy in basic immunological and infectious phenomena is almost entirely due to technological developments in identifying and tracking cells and parasites in vivo, not least through the ability to do this dynamically, in real time through the application of multiphoton microscopy. Here I will outline the background to our own studies applying multiphoton microscopy to analysis of immune priming and tolerance, including studies in the context of infection. These studies highlight the importance of early cellular dialogue in the development of adaptive immune responses and suggest novel biomarkers of health and disease. Finally, I will discuss what developments in imaging are likely to occur, why they are important and what further information these approaches may distill regarding immunity and tolerance pathways.
11:00 – 11:15 Targeting glycosphingolipid biosynthesis normalises T cell function in patients with SLE
Georgia McDonald Centre for Rheumatology Research, Department of Medicine, Rayne Building, University College London, UK
11:15– 11:45 Speakers’ photo then mid-morning break and trade show
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11:45 – 12:15 The role of membrane lipids in the plasticity of T cell responses.
Dr Elizabeth Jury , UCL, London
Membrane lipid microdomains (lipid rafts) play an important role in T cell function by forming areas of high lipid order that facilitate activation. However, their role in regulating T cell differentiation and function remains controversial. I will reveal that by applying a new approach involving microscopy and flow cytometry, membrane lipid order can be characterized in ex vivo primary human CD4+ T cells. Ex vivo CD4+ T cells sustain a gradient of plasma membrane lipid order that influences their function in terms of immune synapse formation, proliferation and cytokine production. Importantly, T cell function can be altered by pharmacologically manipulating membrane order. This could represent a new mechanism to control T cell functional plasticity, raising the possibility that therapeutic targeting of membrane lipid order could direct altered immune cell activation in pathology.
12:15 – 12:30 Interaction with activated monocytes enhances cytokine expression and suppressive capacity of human memory Tregs
Gina Walter, Centre for Molecular and Cellular Biology of Inflammation (CMCBI), Guy’s Campus, King’s College London
12:30 – 13:00 The role of soluble CTLA-4 in immune regulation
Dr Frank Ward, University of Aberdeen, Scotland
It is generally accepted that the CTLA-4 receptor isoform is crucial in regulating effector T cell responses, while alternatively spliced secretable soluble CTLA-4 has rarely been considered in this context. Here I present evidence that sCTLA-4 is actively secreted by T cells during antigen driven immune responses and contributes to extrinsic regulation of these effector responses. To analyse sCTLA-4 function, we developed a monoclonal antibody that selectively binds only the soluble isoform of CTLA-4. Analysis of sCTLA-4 in mice and human effector responses has revealed that functional blockade of sCTLA-4 offers potential for therapy in both cancer and autoimmune disease.
13:00 – 14:00 Lunch and trade show
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14:00– 15:00 Question and Answer Session
Delegates will be asked to submit questions to a panel of experts. Questions can be submitted before the event or on the day
15:00 – 15:30 In depth characterization of autoreactive CD8 T cells responses in Type 1 Diabetes – twist of faith.
Dr Ania Skowera, King's College London, UK
There is considerable evidence that the cytotoxic CD8 T cell response against β-cell peptides has the most direct role in pancreatic β-cell death in Type 1 diabetes. We have identified a highly distinctive HLA A*0201-associated peptide epitope derived from the preproinsulin (PPI) signal peptide 15-24 that exhibits glucose-dependent presentation on the surface of human β-cells in vitro. A CD8 T cell clone specific for PPI15-24 has a TCR that binds with much lower affinity (>270µM) compared to typical virus responses (KD 0.1-10µM) hence it is challenging to study such cells in disease. We have made significant progress in all these aspects by utilizing high-end technology to reveal key characteristics of autoreactive T cell clones including a crystal structure specific of the tri-molecular complex, phenotypically characterized the cells from in peripheral blood, started to dissect their clonotypic repertoire and addressed the mechanism via which autoreactive CD8 T cell clones can kill islet cell targets. This work aims to provide novel, in depth insight into autoimmune processes and offers strategies for immune intervention and prevention of the disease.
15:30 – 16:00 Afternoon Tea/Coffee and trade show
16:00 – 16:30 Decreased cutaneous Immune responses with age: are Tregs to blame?
Dr Milica Vukmanovic-Stejic, UCL Medical School, UK
Immunity declines during ageing, leading to increased incidence and severity of infectious diseases such as pneumonia, meningitis, urinary tract infections, and influenza. Cutaneous immunity is also impaired, as evidenced by increased incidence and severity of malignancy and infection in the skin of older subjects. We studied responses to intradermal antigen challenge in young and old subjects and found that old individuals have decreased ability to respond to tuberculin PPD, candida albicans and VZV. This reduced responsiveness to Ag-challenge involves defects in the initiating events, decrease in proinflammatory cytokine secretion and possibly defective immune survaillance by memory T cells. Interestingly in old individuals proportion of Foxp3+ cells was significantly higher both in the normal skin and throughout the response following Ag- challenge suggesting that they may contribute to these defects.
16: 30 – 17: 00 Bring me sunshine....how environmental factors can control immune regulation.
Professor Robert Barker, University of Aberdeen
Many immune-mediated diseases are associated with low levels of vitamin D and sunlight. To test the hypothesis that ultraviolet light modulates human immune function, the effects of exposure on circulating 25-hydroxyvitamin D, regulatory T cell numbers and immune function were assessed in patients being treated for skin disease. The results demonstrate that narrow band UV therapy increases circulating regulatory T cell numbers and activity in humans, and that vitamin D status appears to be a key determinant of these changes. These findings have important implications for further studies of phototherapy and public health advice regarding vitamin D supplementation, and more broadly for understanding the aetiology of autoimmune and inflammatory diseases.
17:00 Chairman’s summing up
About the Speakers
Robert Barker holds a personal Chair in Immunology and leads the Immunology and Inflammation Research Programme at the University of Aberdeen. His research has for many years focused on the study of immune-mediated diseases, using red blood cells as model target antigens. The lessons learnt have now been extended to further understand the pathogenesis of a wide range of diseases in which the immune system plays an important role, including autoimmune haemolytic anaemia; haemolytic disease of the newborn; immune-mediated thrombocytopenia; Goodpasture’s disease; bullous skin diseases; atopy and asthma; viral and tumour immune evasion. The aim is to be able to control these diseases by manipulating immune regulation, particularly as mediated by regulatory T lymphocytes, and a number of projects are now undergoing commercial development for human trials. Professor Barker is currently a Trustee of the British Society for Immunology, the Groups' Secretary of the British Society for Immunology, and a British Society for Immunology Autoimmunity Affinity Group Committee Member. He also serves as a member of the Research Committee of the Arthritis and Rheumatism Campaign.
Ania Skowera trained in Jagiellonian University in Krakow in Poland. , Initially obtaining her masters and then moved to London. Her PhD at Kings’ College London was on immune activation in Gulf war-related illness. She then began to pursue an interest in autoimmune disease such as Type 1 Diabetes focusing in particular on autoreactive CD8 T cells. She has identified a highly distinctive HLA A*0201-associated peptide epitope derived from the preproinsulin (PPI) signal peptide 15-24. She has Then isolated a first autoreactive PPI15-24-specific CD8 T cells clone from a patient that exhibits glucose-dependent killing of human β-cells in vitro. This work was recognized by aawarded with Juvenile Diabetes Research Foundation (JDRF) Research Scholar Award.
David Wraith trained as an immunologist: since 1982 he has worked in the field of T cell biology and the role of T lymphocytes in protection from infection and in autoimmunity. His laboratory in Bristol focuses on the mechanism of antigen-specific immune desensitization. They have designed peptides for treatment of multiple sclerosis and conducted clinical trials of their use. His laboratory is currently defining the differentiation pathway of antigen induced Treg cells, focusing on the role of specific genes including IL-10 and CTLA-4.
1) Verhagen, J., Gabrysova, L., Minaee, S., Sabatos, C.A., Anderson, G., Sharpe, A.H. and Wraith, D.C. Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4 deficient mice from CNS autoimmune disease. Proc. Natl. Acad. Sci. (USA) (2009) 106: 3306-3311
2) Gabrysova, L., Nicolson, K.S., Streeter, H.B., Verhagen, J., Sabatos-Peyton, C.A., Morgan, D.J., and Wraith, D.C. Negative feedback control of the autoimmune response through antigen-induced differentiation of IL-10-secreting Th1 cells. Journal of Experimental Medicine (2009) 206: 1755-1767
3) Wraith, D.C., Pope, R., Butzkueven, H., Holder, H., Vanderplank, P., Lowrey, P., Day, M.J., Gundlach, A.L., Kilpatrick, T.J., Scolding, N. and Wynick, D. A role for galanin in human and experimental inflammatory demyelination. Proc. Natl. Acad. Sci. (USA) (2009) 106: 15466-15471
4) Gabrysova, L. and Wraith, D.C. Antigenic strength controls the generation of antigen-specific IL-10-secreting T regulatory cells. European Journal of Immunology (2010) 40: 1386-1395
5) Sabatos-Peyton, C., Verhagen, J. & Wraith, D.C. Antigen-specific immunotherapy of autoimmune and allergic diseases. Current Opinion in Immunology (2010) 22: 609-615
Elizabeth Jury, an Arthritis Research UK Career Development Fellow, has worked at the Centre for Rheumatology Research, UCL since 2000. In this time she has opened up new avenues of research into signaling abnormalities in T and B cells from patients with SLE and RA making significant contributions towards understanding the nature of thesse abnormalities and how they relate to disease pathogenesis. The main focus of her research is to understand the role of plasma membrane, cellular and serum lipids on immune cell activation with the long-term aim to identify new targets for development of novel therapeutics.
Prior to an academic career Dr Frank Ward spent nine years at ICI Agrochemicals where he operated as part of team that researched and developed fungicide leads. Later, he completed a PhD and worked as a postdoctoral researcher at King’s College London, investigating the molecular processes important for immunological tolerance in systemic lupus erythematosus. As a lecturer at the University of Aberdeen, he has focussed on the role that natural soluble CTLA-4 plays in these tolerogenic processes.
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