The Academic Department of Rheumatology, a department of DIIID, has long been recognised as one of the premier Rheumatology units in the UK, and one of the most popular training centres for aspiring young academic clinicians. Historically, the Faculty is best recognised for their expertise in Outcomes Research, Genetic Epidemiology, Clinical Trials, Immunology and for having an internationally recognised centre for the management of patients with complex systemic connective tissue disease. In 2008, DIIID recruited two Professors (Frederic Geissmann and Andrew Cope) and established a new Centre occupying 1200 sqm of laboratory space on the 1st Floor of New Hunt's House. The mission of the Centre for Molecular and Cellular Biology of Inflammation (CMCBI) is to discover new fundamental molecular and cellular mechanisms of inflammation and its associated pathologies, exploiting cutting edge models and tools — both experimental and computational — to explore new avenues in the understanding, diagnosis and treatment of Inflammation. The role of genetic variation and how this contributes to the chronic inflammatory process is a major field of study.
Much of the basic laboratory research of the Academic Department of Rheumatology is now incorporated into the Centre. In its broadest sense, the lab seeks to understand at the molecular and cellular level pathways of T cell activation and differentiation that promote autoimmunity, and which contribute to the persistence of chronic immune and inflammatory responses. In recent years, research has focussed on investigating the impact of altered T cell antigen receptor signaling (TCR) thresholds on pathways of T helper cell activation, differentiation and cytokine gene expression and pathways of cell migration. This field of work has been further inspired by the results of genome wide association studies (GWAS) that point unambiguously to the fact that many autoimmune susceptibility genes regulate, directly or indirectly, the specificity or amplitude of signals transduced through the TCR. Perturbations of TCR signals, in turn, regulate activation and differentiation of T cells. Using a combination of in vivo and in vitro models our work has sought to define how allelic variants of immunologically important genes, such as HLA-DRB1, CD3Z, PTPN22 and IL2RA contribute to the pathogenesis of chronic inflammatory autoimmune diseases such as rheumatoid arthritis and lupus.
The Department also hosts the King's Musculoskeletal Clinical Trials Unit (KMS-CTU), based on the Denmark Hill Campus. KMS-CTU, a UKCRC registered clinical trials unit, coordinates a broad portfolio of both investigator-led and commercial interventional and observational studies, with a particular focus on inflammatory arthritis. In recent years the Unit has led several multi-centre clinical trials of combination disease modifying drugs e.g. CARDERA and TACIT studies and is now recruiting to a UK wide study of drug tapering of biological therapy - the OPTIRRA study. In February 2012, the unit was awarded Arthritis Research UK Experimental Arthritis Treatment Centre status. New interventional studies are currently aimed at defining therapeutic strategies that induce immune tolerance. Health outcomes research has also been a major priority. More recent cohort-based studies seek to characterize by deep clinical and immune phenotyping low disease activity states. These studies are aimed at defining, at an immunobiological level, disease remission in patients with RA. Finally, exciting new approaches are being sought to define RA during the pre-clinical phase of disease, with the intention of targeting high risk subjects for preventive therapy, and potentially cure.
My research is undertaken as part of the clinical arm of the Academic Rheumatology Research Group led by Professor David Scott at Denmark Hill though there is close collaboration with other Academic Rheumatology Group members, with other local Trusts and with the Rheumatology Specialty Group of the local Comprehensive Local Research Network.
The research is funded by a variety of agencies including Arthritis Research UK and the NIHR and involves both primary (trials and observational studies) and secondary (systematic reviews) studies.
Clinical research in inflammatory arthritis
1) Clinical trials examining the role and relative effectiveness of disease modifying drugs and biologic in rheumatoid arthritis and spondyloarthropathies
2) Observational research on patient-derived, clinical and other outcome measures and prognostic markers in inflammatory arthritis
Health services research in inflammatory arthritis
1) Patient's perspective of primary and secondary care rheumatology and musculoskeletal services
2) Evaluation of service improvements and innovation in inflammatory arthritis and other rheumatology services
Other musculoskeletal diseases
Similar projects in soft tissue rheumatic diseases
My research areas include rheumatic disease epidemiology and clinical trial design. In particular I am working to develop the King’s Early Phase Clinical Trial Portfolio with a focus on developing treatments to treat or, hopefully in the future, prevent rheumatoid arthritis.
Main focus of research is that of immune regulation by heat shock proteins (stress proteins) in inflammatory disorders (mainly rheumatoid arthritis, inflammatory bowel disease and cardiovascular disease).
Modulation of inflammatory arthritis with the stress proteins HSP60 and BiP.
Antigen-specific CD4+ T cells appear to be a central component in the pathogenesis of a variety of human autoimmune diseases and animal models of autoimmunity. Such T cells can home to the target tissue where autoantigen is present and, after local activation, produce pro-inflammatory cytokines. These events lead to the recruitment and activation of both lymphocytes and monocytes that ultimately destroy the target tissue. Consequently, a search for antigens which could initiate and/or perpetuate T cell responses in arthritic joints is continuing. The characterisation of target antigens in autoimmune diseases is an important step towards understanding the aetiology of this group of conditions, and in designing specific immunotherapeutic regimes. Two such antigens identified in separate studies are the 60kD heat shock protein (hsp60) and the 70kD stress protein BiP. Surprisingly, immune responses to both these proteins are not pro-inflammatory but are instead classified as anti-inflammatory or regulatory. Hence continuing studies aim to utilise their regulatory potential to develop novel immunotherapeutic interventions in inflammatory diseases such as rheumatoid arthritis.
Circulating cell stress proteins, leukocyte function and cardiovascular disease.
There is growing evidence for the hypothesis that plasma levels of extracellular molecular chaperones, such as Hsp60 or Hsp70 correlate (positively or negatively) with susceptibility to coronary heart disease and stroke. The biological consequences of having high blood levels of such proteins are unknown. Nor have associations with subclinical coronary artery disease and risk of clinical cardiac events been established. Recent evidence has revealed that human lymphocytes are exquisitely sensitive to certain molecular chaperones with both activation and inhibition of cell function being found in vitro. The hypothesis being tested is that individuals with high levels of molecular chaperones in their circulation will evoke changes in lymphocyte function that may predispose to organ, particularly cardiovascular, pathology. This is being tested in studies combining molecular biological, immunological and epidemiological methods with cardiac imaging in a subset of the Whitehall II epidemiological cohort (a large group of civil servants who have had the development of any heart disease monitored over the past 15-20 years).
Our present laboratory projects focussed on BiP include the following:
Search for the cell surface expressed receptor(s) for BiPInvestigation of the mechanism by which BiP directly affects T cells and DC inducing regulatory T cells and tolerogenic DC respectively.Future work will incorporate projects looking at the efficacy of BiP in osteoporosis and transplantation where preliminary in vitro data shows that BiP has therapeutic potential
As a translational project BiP has preliminary approval by the MHRA for a PhaseI/IIa clinical trial.
Research in Immunobiology seeks to elucidate the development, function and regulation of immune cells by applying diverse experimental approaches including molecular and cell biology, transgenic and molecular genetics, including the use of fruit-flies, and state-of-the-art analysis of human samples. Key interests include pathways of lymphocyte and myeloid cell development; mechanisms of autoimmunity; tumour surveillance; the response to virus infection; vaccine and adjuvant development, particularly with respect to HIV; gut B cell biology; and the relationship of immunological and inflammatory processes to metabolism and to ageing. The research teams collectively publish their results in journals of the highest standing such as Science, Nature Immunology, Immunity, Journal of Clinical Investigation, and Journal of Experimental Medicine.
Professor Adrian Hayday: a major focus is on intraepithelial lymphocytes (IEL) – a very large yet poorly understood T lymphocyte compartment residing constitutively within tissues. Compared to their well-studied systemic counterparts, IEL undertake rapid surveillance of molecules denoting tissue dysregulaion, associated with infection, inflammation, and malignancy. The laboratory investigates the molecules and mechanisms underlying such “lymphoid stress-surveillance”, with the potential of IEL to form a novel target for clinical intervention.
Professor Frederic Geissmann: the laboratory aims to define the major pathways of monocyte, macrophage, and dendritic cell (DC) development, and to understand how these cells affect basis physiologic processes, such as metabolism, as well as their roles in innate and adaptive immunity.
Professor Mark Peakman: the structural basis for T cell recognition of human pancreatic antigens in Type 1 diabetes; the mechanisms by which genetic susceptibilities to Type 1 diabetes operate in relation to MHC genes and genes affecting immune regulation; the development of peptide immunotherapy.
Professor Jo Spencer: the function of intestinal IgA is to maintain homeostasis in the lumen of the gut, which is rich in microorganisms and toxins. IgA coats the diverse luminal contents thus agglutinating and stabilising them. Thus, IgA must be both abundant and diverse in its binding repertoire. Our research focuses on how IgA responses are generated and diversified, and how specific responses to intestinal immunisation might be achieved. We examine how the impact of diet and the microbiota on intestinal B cell biology may regulate systemic autoimmunity.
Dr Marie Bijlmakers: antigen recognition by T cells initiates multiple signaling pathways leading to cell proliferation and differentiation. Ubiquitination is an important regulatory mechanism in many cellular processes. The laboratory studies the ubiquitination of key molecules in T cells, such as the tyrosine kinase Lck, and the role of a novel family of ubiquitin ligases genetically implicated in the common inflammatory disease, psoriasis.
Dr Helen Collins: TB remains a major global scourge. Starting from the dependence of mycobacterial infection on metal ions, our laboratory studies mechanisms by which metal ions profoundly influence T cell biology. The development of novel ion chelators may provide a new class of immunosuppressants.
Dr Sandra Diebold: the development of novel cancer vaccines by forming conjugates of antigens, DC-targeting molecules and synthetic mimics of viral nucleic acids. Basic studies into how DC function is affected by cell and tissue damage associated with inflammatory and infectious scenarios.
Dr Marc Dionne: the laboratory employs Drosophila genetics to identify key pathways regulating inflammatory cell behaviour, with focus on how the balance is achieved between positive contributions to host protection against mycobacteria and the negative contributions to tissue damage and inflammatory disease.
Dr Deborah Dunn-Walters: next generation sequencing is employed to define the immunoglobulin repertoire associated with ageing, with different tissues, with vaccination, and with different pathologies. How are key specificities generated and regulated? This can guide strategies to improve vaccination success in vulnerable populations.
Dr Pierre Guermonprez: the impact of infection on the development and functional responsiveness of DC and monocytes; the regulation of monocyte, macrophage, and DC function by lipid bodies and the relationship to artherosclerotic disease where failure of this system may alter key scavenging activities.
Dr Susan John: the IL-2/IL-2 receptor complex is the primary growth factor axis for T cells. Despite intensive study, there is only partial understanding of how its major signaling mediators, Stat5a and Stat5b, profoundly affect T cell biology. The lab identifies and characterizes targets of Stat5 activation in health and disease, and has thereby identified a novel mechanism of T cell regulation.
Dr Linda Klavinskis: HIV1 is currently responsible for more deaths than any other infectious agent, and yet we have neither an effective vaccine nor prophylactic antiviral agents accessible to most of those at risk. Our research aims to increase understanding of how different innate signals, mediated by distinct DC functions, dictate the magnitude of the CD8 T cell memory pool, which is critical in developing effective vaccines. We aim thereby to design better vaccine immunogens and delivery vectors to elicit systemic and mucosal neutralising antibody and T cell responses.
Dr Leonie Taams: using human cells and clinical materials, coupled with high-resolution imaging, the laboratory investigates molecules and pathways by which monocytes regulate the balance of regulatory T cells, and potentially pathogenic, interleukin-17-producing cells, with particular focus on Rheumatoid Arthritis.
Dr Tim Tree: building on recent advancements in understanding peripheral T cell regulation, the laboratory’s research identifies immunoregulatory mechanisms that fail in Type I diabetes. Through collaboration with a large genetics resource in Cambridge, a new level of correlation can be established between immunophenotyping and genotyping, thereby elucidating pathways of pathogenesis. Parallel clinical studies investigate whether immunoregulatory mechanisms can be restored in diabetes-prone or islet transplanted individuals through immunotherapeutic interventions.
Defining the molecular interactions and signalling events at the monocyte and endothelial cell interface in vivo
The Dept of Infectious Diseases undertakes diverse programmes of research aimed at advancing our understanding of the complexities of viral and bacterial pathogenesis. Our research therefore leverages broad strengths in molecular, biochemical, structural, cell biological and immunological approaches for understanding pathogen replication with patient-based, epidemiological and Biobanking expertise in the areas of microbiology, virology and sexually transmitted diseases. Considerable effort is devoted to HIV/AIDS, with particular interests in innate immune mechanisms, virus assembly, host-virus interactions and novel strategies for imaging infections in vivo. We have further interests in parvoviruses and their potential exploitation as vehicles for the genetic manipulation of stem cells, and are currently expanding our portfolio to additional viral systems. We are also undertaking a multicentre clinical trial that addresses the management of severe bacterial infections, which will provide the platform for a variety of future clinical and laboratory-based projects.
Clinical trials in HIV infection; especially immunopathogenesis, vaccine,metabolic and drug trials.
virus-host interactions during HIV-1 infections. Interests include host restriction factors, factors that support HIV-1 replication and the metabolic demand exerted by HIV infections.
The two main research projects focus on understanding mechanisms of staphylococcal (predominantly methicillin-resistant Staphylococcus aureus MRSA) disease pathogenesis and transmission in the hospital setting.
I am interested in understanding the mechanisms by which mammalian cells coordinate the reorganization of their cytoskeleton with membrane remodeling events, a key step during physiological processes like viral infection and the last steps of cell division. For this purpose we are using comprehensive and interdisciplinary experimental methods in cell biology and virology.
The impact of infection on the development and functional responsiveness of DC and monocytes; the regulation of monocyte, macrophage, and DC function by lipid bodies and the relationship to artherosclerotic disease where failure of this system may alter key scavenging activities.