Academic Rheumatology
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.
