NIHRDataInsights/HRCSData huggingface dataset:
Title: Do regulatory T cells mediate the therapeutic effect of anti-TNF antibodies in inflammatory arthritis.
Funder: Arthritis Research UK

Abstract: We have demonstrated that natural regulatory T cells (Treg) from patients with active rheumatoid arthritis (RA) are defective. Infliximab, rather than restoring this defect, can induce a distinct and potent population of adaptive Treg in responding patients. This data has led us to propose that the therapeutic effect of infliximab is mediated through the induction of Treg. Since we are unable to formally test this hypothesis in patients, we will utilize the collagen induced arthritis (CIA) experimental model to dissect the interaction of anti-TNF therapy and Treg in vivo. Our unpublished data suggest that etanercept does not increase Treg numbers. Therefore, we will compare the impact of different modalities of TNF blockade on Treg in CIA in order to reveal alternate mechanisms of action. The demonstration that we can target Treg in vivo, and that their manipulation underpins the mechanism of action of anti-TNF, in patients with RA will have huge implications on how we design better treatments for this debilitating disease.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining the effect of gamma delta T cells on osteoclasts and its relevance to inflammation-induced bone loss
Funder: Arthritis Research UK

Abstract: Rheumatoid arthritis is a chronic inflammatory disease caused by deregulated immune cell function. A specific subset of T cells, gd T cells, are found in the inflamed joints of RA patients but their role in the disease process of RA and bone homeostasis is currently ill-defined. Recently, gd T cells have been demonstrated to produce IL-17 and play an active role in the disease process of autoimmune arthritis in a murine model. IL-17 stimulates the production of the crucial osteoclast differentiation and survival factor RANKL, thereby linking T cell activation with bone destruction in RA. However, gd T cells can also produce other cytokines which may have anti-osteoclastogenic effects. It is the aim of this fellowship to determine the ability of human gd T cells to modulate osteoclast behaviour in both normal and RA disease states and to clarify the role of these T cells in RA.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Integrated serological and genetic studies in idiopathic inflammatory myopathies (IIM) to investigate disease mechanisms and better define clinical outcomes.
Funder: Arthritis Research UK

Abstract: Careful investigation of disease mechanisms, refinement of diagnostic classification and tools to aid earlier diagnosis are urgently required to improve outcome in adult and juvenile IIM. We will investigate immunogenetic associations of new/existing IIM autoantibodies, characterise additional novel autoantigen systems and investigate myositis-specific autoantigen expression in cell lines and IIM lesional tissue, to ultimately develop solid based assays for routine novel/existing IIM autoantibody testing. Findings from a genome wide association study will be pursued as follows: 1) replication of single nucleotide polymorphisms with strong evidence for association from the GWAS and other autoimmune diseases in an independent UK/European IIM cohort; 2) resequencing and fine-mapping of replicated loci to identify likely functional variants. A prospective biobank for future IIM tissue expression work and functional studies will be established. Integration of genotype, serotype and clinical phenotype is of fundamental importance to optimise future treatment strategies and thus improve clinical outcome in IIM.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Accurate phenotyping in early arthritis to improve prognosis and prevent evolution to rheumatoid arthritis (Renewal)
Funder: Arthritis Research UK

Abstract: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory arthritis (IA), affecting 400,000 people in the UK and is the largest cause of treatable disability in the Western world. Traditionally, RA was perceived to have a fixed phenotype with a linear progression of destruction. Recent evidence, however, suggests that RA is just one endpoint in the early IA disease continuum. Crucial developments have confirmed the real possibility of identifying and classifying people with early IA, to determine those who will progress to RA or undifferentiated IA, enabling intervention to influence evolution. This proposal aims to explore several biomarkers particularly imaging, where new technologies are emerging, for their predictive value; additionally auto-antibodies, genetic, serological and cellular candidates will be used in combination to identify key points in the development of RA. This proposal will offer a real possibility of identifying patient sub-groups for whom intervention will slow/prevent evolution to persistent damaging disease.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Metabonomic analysis in early arthritis
Funder: Arthritis Research UK

Abstract: The fellow will investigate the hypothesis that metabolite profiles in early arthritis patients can predict the future course of the disease. Using NMR spectroscopy, the metabonomic profile of serum, urine and synovial fluid from patients with early synovitis will be stratified using multivariate analysis. The profile, and identifiable metabolites, will be related to clinical parameters, and established predictors of outcome such as RF and anti-CCP antibody, along with cytokine profiles derived using bead-based arrays. Metabolites derived from in vitro cultures of synovial fibroblasts will be mapped onto those identified ex vivo to identify specific metabolic pathways perturbed in inflammatory arthritis. Stored blood and synovial fluid will be used to develop a predictive model which will then be tested on prospectively collected samples. The application of this novel approach to the prediction of outcome will provide an excellent training in this important and growing area of post-genomic disease analysis.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A Randomized Controlled Clinical Trial Of Anti-B-Cell Therapy In Patients With Primary Sjögren’s Syndrome (The ‘Tractiss’ Study)
Funder: Arthritis Research UK

Abstract: Sjögren’s syndrome is characterized by dry eyes and dry mouth, severe fatigue with reduced quality of life, B-cell hyperactivity, anti-Ro/La antibodies and a 44 times increased risk of B-cell lymphoma. There is no effective systemic therapy. We propose a phase-III study of 110 patients treated with either rituximab or placebo with re-treatment at 6 months. Pilot data in two double-blind randomised controlled pilot studies suggests benefit. In parallel with the clinical outcomes of improvement in fatigue and/or dryness we propose a number of biological outcomes including glandular immunohistochemistry and genetic features, alteration in anti-muscarinic antibody levels, peripheral T-cell numbers and function and B-lymphocyte stimulating factor levels. The trial is proposed by a group who have led the development of clinical assessment tools in this condition with a track record of successful patient recruitment, in collaboration with leading UK rheumatology research units and run by an experienced UK clinical trials unit.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Optimising Treatment With Tumour Necrosis Factor Inhibitors In Rheumatoid Arthritis: Is Dose Tapering Practical In Good Responders? A Proof Of Principle And Exploratory Trial (OPTTIRA)
Funder: Arthritis Research UK

Abstract: Tumour necrosis factor (TNF) inhibitors are effective and safe in rheumatoid arthritis (RA). An important, overlooked question is how best to maintain response after disease control is achieved. We consider “maintenance therapy” with TNF inhibitors requires lower doses than “induction” therapy in active established RA. We believe this will increase the cost-effectiveness of TNF inhibitors and may also reduce the risk of serious adverse events. As there no evidence, outside small case series, TNF inhibitor dose-tapering is possible in established RA. We therefore propose a dose-ranging “proof of principle” trial in which TNF inhibitor doses are tapered by both one-third and two-thirds of those used to induce responses. The trial will ensure dose tapering does not cause more flares and evaluate its impact on disease activity and cost-effectiveness. If dose-tapering is successful exploratory extension studies will expand the evidence for dose tapering and assess if further reduction is possible.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Optimal treatment of RA patients requiring Biologic therapy (ORBIT)
Funder: Arthritis Research UK

Abstract: Anti-TNF therapy is licensed for the treatment of patients with severe RA that are resistant to conventional disease-modifying antirheumatic drugs (DMARDs), and NICE/SMC have recommended the use of these drugs in the NHS according to the British Society for Rheumatology (BSR) guidelines. Rituximab is a monoclonal anti-CD20 antibody that causes depletion of CD20 +ve B-cells, and is effective and licensed for the treatment of patients with severe, active RA who have failed to respond to at least one anti-TNF drug; NICE/SMC have approved the use of rituximab in the NHS in this context. If/when a license is granted to rituximab for use in patients who have failed to respond to DMARD therapy, but have not yet been tried on anti-TNF therapy, clinicians will face a choice of biologic targets to use first – TNF antagonism or B-cell depletion. This randomised controlled trial should provide clinicians and NICE/SMC with direct evidence regarding the relative efficacy and cost-effectiveness of these strategies


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The Long-term Safety and Efficacy of Biologic Therapies in Children with Rheumatic Diseases
Funder: Arthritis Research UK

Abstract: Biologic therapies have improved outcomes for children with severe juvenile idiopathic arthritis (JIA). However, their long-term effects remain understudied. Data on long-term outcomes following etanercept therapy, the only drug licensed for JIA, are already being collected. Increasingly, other biologic drugs licensed only in adults are being used in children when etanercept may not be the best choice, such as children with systemic arthritis or in those with uveitis. The response to these drugs and their long-term safety has not been well studied during routine clinical use. This study aims to prospectively recruit a cohort of UK children receiving alternative biologic agents to study their effectiveness and safety. The rates of adverse events will be compared with a cohort of biologically-naive children starting methotrexate. In addition, a BioBank will be established, collecting samples from children receiving all biologics in the UK, such that predictors of response, including genetics, can be studied.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of syndecan-integrin cross-talk in regulation of endothelial cell function in leukocyte migration and angiogenesis.
Funder: Arthritis Research UK

Abstract: Leukocyte infiltration and angiogenesis are key features of chronic inflammatory conditions such as rheumatoid arthritis. These responses are regulated through activation of endothelial cells (ECs) by exogenous stimuli as well as the interaction of ECs with extracellular matrix (ECM) proteins. The latter is primarily mediated via integrins however other receptors are also of importance including syndecans and the protein tyrosine phosphatase receptors (PTPRs). My work to date has demonstrated that syndecans can stimulate integrin-mediated cellular responses via interactions with PTPRs. I now propose to investigate the role of these novel interactions in regulation of signalling events that mediate EC responses in the context of leukocyte migration and angiogenesis. Specifically, the project aims to investigate the role of syndecans -2 and -4 (both expressed in ECs) in EC/leukocyte and EC/EC interactions in vitro and the role of syndecans in leukocyte migration and angiogenesis in vivo as studied using syndecan deficient mice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of MicroRNAs in monocyte and macrophage activation and effector function in rheumatoid arthritis (RA)
Funder: Arthritis Research UK

Abstract: Macrophages are a predominant source of cytokines that drive RA synovitis. Recently a new class of regulators of transcription called microRNA has been described that regulates expression of proteins that operate in biologically coherent pathways - as such they represent an exciting potential therapeutic target to modulate effector pathways in complex systems such as RA synovitis. Dysregulated miRNA expression has been described thus far mainly in cancer and cardiovascular diseases; altered synovial miRNA expression is also described, particularly in the context of fibroblast biology. The role of miRNAs in regulating synovial macrophage effector function is unknown. I shall therefore perform a systematic characterisation of RA macrophage miRNA expression. Thereafter I shall define miRNA with critical regulatory function in effector cytokines production in model systems in vitro and in the generation and perpetuation of arthritis in vivo. Together these studies will determine the potential for miRNA as new targets in RA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Evaluation of the sensitivity to change of the LupusQoL, a disease-specific health-related quality of life (HRQoL) measure
Funder: Arthritis Research UK

Abstract: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that causes considerable morbidity and mortality. It predominantly affects women during the reproductive years and is characterised by relapses and remissions. With the development of new therapies it is critical to demonstrate if these interventions improve health-related quality of life (HRQoL). We have developed a disease-specific HRQoL measure, the LupusQoL which has good validity and reliability. However, the sensitivity to change of the LupusQoL is untested. The main aims of this proposal are to evaluate the sensitivity to change and to estimate the minimal clinically important difference for SLE patients of the LupusQoL and to compare these to the SF-36 generic health survey. If the LupusQoL demonstrates sensitivity to change then it can be used in clinical trials for new therapies as it should provide a more comprehensive and discriminating HRQoL outcome measure than the currently available measures.


Research activity codes: 7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Endogenous soluble CTLA-4 as a regulator of autoreactive pathogenic immune responses in systemic lupus erythematosus
Funder: Arthritis Research UK

Abstract: Systemic lupus erythematosus (SLE) is a common and serious autoimmune disease, for which current treatments are unsatisfactory. The CD4+ T cells that are thought to drive pathology are attractive therapeutic targets, and this project focuses on a new pathway to inhibit their activity. Soluble CTLA-4 (sCTLA-4) is a little studied alternative isoform of membrane-bound CTLA-4, a negative costimulatory molecule expressed by activated T cells and regulatory subsets. We have shown previously that sCTLA-4 is secreted by T cells from healthy donors in response to foreign antigen, and that it strongly inhibits specific immune responses. The aim is to characterise this novel inhibitory mechanism in SLE. We will measure sCTLA-4 production by T cells from SLE patients to test whether it is secreted in response to autoantigen and can control autoaggressive immune responses. The T cell subset(s) that secrete sCTLA-4 will be identified, and, in particular, it will be determined whether regulatory T cells are a prominent source. Finally, the relationships between reduced sCTLA-4 production, SLE, and inheritance of a susceptibility allele that may control its production, will be established. This work will be a first step in establishing sCTLA-4 as a potential therapeutic target and biomarker in SLE.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Elucidating the role of TRPA1 in modulating joint inflammation and pain
Funder: Arthritis Research UK

Abstract: Transient receptor potential (TRP) receptors are thermo-sensing, ligand-gated non-selective cation channels that mediate pain and inflammation. We and others have presented evidence for the role of TRP vanilloid 1 (TRPV1) channel in arthritis. We now have new evidence that the co-localised TRP ankyrin1 (TRPA1) channels are also involved in pain processing in murine CFA-induced mono-arthritis and may have potent vascular effects in the joint. We hypothesise that TRPA1 plays an important role in arthritis. This project involves use of a range of experimental tools and wild type and TRPA1 knockout mice to address the following questions: 1) how do TRPA1 agonists influence hyperalgesic sensitivity and does a reduced ambient temperature enhance TRPA1-mediated pain sensitivity? 2) do TRPA1 agonists also contribute to vascular inflammation in the joint whilst also signaling to higher nervous centres? 3) does TRPA1 deletion affect the profile of pain and inflammation in collagen-induced arthritis, a well documented model of human arthritis? 4) is blockade of arthritic symptoms enhanced in double (TRPA1 & TRPV1) knockout mice, as compared with single knockout mice? These studies are essential for the evaluation of TRPA1 as a potential target for a novel therapeutic agent to combat arthritic pain and inflammation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: B-INKT cell cross-talk: pointing iNKT cells to the right direction.
Funder: Arthritis Research UK

Abstract: CD1d-restricted invariant natural killer T (iNKT) cells function during innate and adaptive immunity and despite their relatively low number, are believed to play a potent immuno-regulatory role in a wide variety of immune responses. Importantly, they have been shown to control: tumour expansion, infectious disease and the development of autoimmune disease including rheumatoid arthritis (RA) (1). Whereas more is known about the outcome of the interaction between dendritic cells and iNKT cells, at present very few studies have examined the influence that B cells presenting lipid-antigen have in the maintenance of iNKT cell proliferation and differentiation. Our preliminary results in the context of experimental arthritis support the hypothesis that B-iNKT cell interaction is important to shape an iNKT cell mediated tolerogenic immuno-response. We will also investigate whether adoptive transfer of B cells that have been stimulated in vitro with agalactosylceramide (aGalCer), a marine-sponge-derived glycolipid known to potently activate iNKT cells (2), can be used to expand iNKT cells in recipient syngeneic mice and whether this can ameliorate arthritis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: 1,25,OH2 Vitamin D3 as a regulator of T cell differentiation and function in Rheumatoid Arthritis
Funder: Arthritis Research UK

Abstract: The way in which T cells respond to antigen stimulation has a significant impact on our propensity to develop autoimmune diseases. It is abundently clear from animal models that inflammatory T cell responses associated with cytokines such as IL-17 drive autoimmune diseases including arthritis. Modulating T cell responses away from such inflammatory outcomes is therefore a promising therapy. We have found that the active form of vitamin D, (1,25 OH2D3) has very powerful modulatory effects on T cells. Not only does 1,25 OH2D3 inhibit the expression of inflammatory cytokines such as IL-17, IFN-γ and Il-21, it also promotes regulatory outcomes such as the expression of FoxP3, CTLA-4 and IL-10. Thus, 1,25 OH2D3 appears to represent an environmentally regulated factor that potently alters T cell responses. We therefore wish to investigate in more detail the extent to which 1,25 OH2D3 can re-program T cell responses and understand the molecular mechanisms associated with this. We will also determine whether various aspects of the vitamin D pathway are intact in patients with rheumatoid arthritis and study its effects on T cell differentiation. Finally, we propose to investigate whether treatment with 1,25 OH2D3 has therapeutic potential in a murine model of arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Clinical evaluation of autoantibodies against gp130 and its soluble variants in inflammatory arthritis
Funder: Arthritis Research UK

Abstract: We have previously demonstrated that interleukin (IL)-6 activity during inflammatory arthritis is reliant on signalling via the soluble IL-6 receptor. This mode of cellular activation is termed IL-6 trans-signalling and governs the synovial recruitment, retention and effector characteristics of the inflammatory infiltrate. Specifically, we have shown using local and systemic models of inflammatory arthritis that selective blockade of this pathway using its natural antagonist soluble gp130 significantly reduces disease. This more targeted approach to blocking IL-6 activity therefore represents a promising therapeutic strategy. To evaluation the true potential of soluble gp130 it is critical that key baseline clinical measurements are next performed. In this respect, our recent investigations have identified that patients with rheumatoid and osteoarthritis display varying incidence of autoantibodies against gp130. The functional significance of these autoantibodies is unknown. We therefore hypothesise that these autoantibodies may influence the therapeutic outcome of IL-6-directed therapeutic strategies. _x000D_ By combining basic and clinical research using in vivo models of arthritis and in vitro cellular and molecular screening approaches, studies will:_x000D_ 1- Define the clinical incidence of anti-gp130 antibodies in rheumatoid arthritis_x000D_ 2- Examine the functional characteristics of anti-gp130 antibodies_x000D_ 3- Compare the potency and efficacy of sgp130 variants in experimental arthritis


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM