NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding palindromic rheumatism: defining the impact, identifying the phenotype and establishing research priorities.
Funder: Arthritis Research UK

Abstract: Palindromic rheumatism (PR) is a poorly understood condition which remains a challenge to patients and clinicians alike. This application is a collaborative, tripartite approach to understanding the drivers of palindromic rheumatism and to build capacity for future research. First, we will explore PR from a patient perspective: in Birmingham, we will conduct qualitative interviews with patients to determine the symptom profile and impact of PR, including issues around uncertain diagnosis and unnecessary treatment. We will identify candidate biomarkers in order to establish predictors for accurate and efficient diagnosis of treatment. Using existing databases in Leeds, we will identify patients with PR and explore candidate biomarkers including serological, imaging (ultrasound and MRI) and immunological assessment. Finally, we will establish a PR Research Network, bringing together four key early inflammatory research centres (Leeds, Birmingham, Newcastle and Glasgow), patient partners (Leeds Musculoskeletal Biomedical Research Unit PPI Group, Birmingham Rheumatology Research Patient Partnership and the Palindromic Rheumatism Facebook Group) and Arthritis Research UK to develop a national collaborative research group who will prioritise research questions and develop a capacity building strategy specifically for PR.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of KIR3DL2-HLA-B27 interactions in the survival and differentiation of pathogenic Th17 cells in Ankylosing Spondylitis
Funder: Arthritis Research UK

Abstract: HLA- (B27) is strongly associated with the Spondyloarthritides (SpA), a group of debilitating arthritic disorders typified by Ankylosing Spondylitis (AS). HLA-B27 is expressed at the surface of antigen presenting cells (APC) both as classical 2m-associated heterodimers and as 2m-free disulphide bonded heavy chain homodimers (termed B27). KIR3DL2 is a member of the killer cell Immunoglobulin-like receptor (KIR) family Our research has suggested a central role for KIR3DL2 –expressing leukocytes in AS pathogenesis. We have observed increased numbers of KIR3DL2-expressing lymphocytes (including CD4 T cells) in SpA patients. These cells are enriched for production of proinflammatory cytokines and chemokines such as IL17 and IL-8. Secondly we have shown that KIR3DL2 binds to B27 more strongly than heterotrimeric class 1, promoting the survival of potentially pathogenic Th17 cells. Lastly inhibiting KIR3DL2 binding to B27 inhibits both the survival of these inflammatory leukocyte subsets and their production of IL17. We propose that KIR3DL2 not only identifies a family of pathogenic lymphocytes (including classical and innate cells) but is also an important therapeutic target._x000D_ _x000D_ We will now identify inhibitory antibodies which block the KIR3DL2 interaction with B27 by screening in a reporter cell assay a panel of anti-KIR3DL2 monoclonal antibodies (MAbs), with defined specificities against different regions of the KIR3DL2 receptor. Subsequently, we will use multiplex cytokine array, ELISA, microscopy and FACS analysis to characterise the effect of these inhibitory anti-KIR3DL2 MAbs on the survival and cytokine production of KIR3DL2-expressing cells from peripheral blood and synovial tissue ex vivo. This work will identifY optimal candidate MAb therapeutics and determine their biological effects ex vivo, in order to enable a decision on progression to human trials.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: In vivo efficacy of selected mesenchymal stromal cell subpopulations for rheumatoid arthritis
Funder: Arthritis Research UK

Abstract: Rheumatoid Arthritis (RA) affects 1% of the UK population and remains a major cause of disability and reduced life expectancy, with annual NHS costs of £560 million, and social costs of £1.8 billion. Poorly controlled inflammation, joint damage and resulting deformity in RA lead to disability, impaired quality of life and reduced life expectancy due to premature cardiovascular disease. Recently developed biological therapies that target lymphocytes and cytokines (TNFα, IL-6) have significantly improved outcomes. However, approximately 20% of patients remain refractory to all treatments, and biological treatments exhibit both significant side effects and a therapeutic ceiling of response of around 70% efficacy in all outcome variables of limited duration. There is a continuing need to discover more effective immune modulating therapies with improved safety profiles._x000D_ Mesenchymal Stromal Cells (MSC) are a mixed population of plastic-adherent (PA) cells isolated from adult bone marrow. PA-MSC secrete potent immunosuppressive and angiogenic proteins; over 100 clinical trials are currently testing PA-MSC in 40 distinct autoimmune and ischemic diseases. Notably, preclinical studies show a single intravenous administration of un-modified PA-MSC can control rodent arthritis, prompting recent clinical safety studies in arthritis patients. We aim to comprehensively examine if MSC can control arthritis in murine models. To facilitate this we identified an antibody (52) that prospectively isolates comparable, equivalent 52+ MSC from human, rat, mouse and rabbit marrow, enabling testing of pure 52+/- MSC and mixed PA-MSC for the first time. Furthermore, separation of PA-MSC into 52+ and 52• fractions reveals functionally distinct populations. We will assess if 52+, 52•, a comparator selected population (ALP+) and PA-MSC exert differing control of inflammation in a murine model of arthritis, accomplishing a critical step in preclinical development.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of MHC protein turnover in autoimmune pathogenesis
Funder: Arthritis Research UK

Abstract: Abnormal protein life spans of disease-associated MHC allelic variants have previously been proposed as one putative mechanism linking MHC polymorphism to autoimmune pathogenesis. In my SRF, this hypothesis was tested by developing novel "SINEW" stable isotope/MS techniques to measure protein turnover rates of MHC allomorphs in physiological settings. We examined HLA-dr4 subtypes associated with RA, B27 subtypes associated with SpA, and Ag7 in the NOD mouse model of spontaneous autoimmunity. MHC class and isotype and extrinsic variables (conformational heterogeneity; APC type and activation state; environmental influences in mice) influenced MHC protein turnover, but in normal APCs, none of the disease-associated allelic polymorphism did. The RPA will enable completion of ongoing work to (1) identify specific proteases that initiate lysosomal HLA-dr breakdown; (2) characterise effects of intestinal microbes on autoimmune disease incidence, immune homeostasis, and Ag7 turnover in NOD mice; (3) test how the life span of citrullinated peptide/dr4 complexes is regulated by the RA-associated "shared epitope"; (4) initiate follow-up studies on the dynamics of B27 misfolding and its impact on the life span of pathogenic CD4 T-cell subsets; and (5) advance analytical techniques and software to enable broader uses of SINEW to probe homeostatic alterations in autoimmunity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Validation of laser Doppler imaging and thermography in patients with Raynaud’s phenomenon secondary to systemic sclerosis
Funder: Arthritis Research UK

Abstract: In systemic sclerosis (SSc), Raynaud’s phenomenon (RP) can affect the digital vasculature so severely that irreversible tissue injury occurs; often leading to ulceration (50% of patients) and more rarely gangrene, requiring amputation (15%). Objective and reliable outcome measures for clinical trials of novel drugs to treat RP are currently lacking. Laser Doppler imaging (LDI) and thermography are two non-invasive measures of blood flow that show excellent potential but require further validation in order to prove their suitability as outcome measures._x000D_ Our main aim is to determine and compare the reproducibility and validity of LDI and thermography, testing the hypothesis that both methodologies are sufficiently reproducible and valid to allow their use as outcome measures in multi-centre clinical trials._x000D_ 180 patients with RP secondary to SSc will be recruited from seven specialist UK centres. They will be invited to attend to undergo a cold challenge to invoke decreased blood flow prior to reperfusion/rewarming at room temperature on two consecutive days. The change in blood flow will be measured by LDI and thermography.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Developing clinically useful biomarkers for diagnosis and prognosis of early undifferentiated arthritis
Funder: Arthritis Research UK

Abstract: There is general agreement that patients with rheumatoid arthritis (RA) have the best outcome if treated at the earliest opportunity. Undifferentiated arthritis (UA) is a step along the inflammatory arthritis disease continuum towards RA. It is therefore vital to make the diagnosis of UA as early as possible to instigate therapy. Currently it is very difficult both to make a diagnosis of UA in people presenting with only inflammatory symptoms and to predict their prognosis and treatment response. My previous work has provided experience in understanding MRI and ultrasound (US) as biomarkers for UA/early RA, especially in very early disease, and my research programme aims are to explore novel imaging (3T MRI and US) and soluble biomarkers for very early diagnosis and prognosis of UA._x000D_ Since starting my Clinician Scientist fellowship, I have recruited a new onset UA cohort (n=100), with RA comparators, in order to (1) Document and quantitate MRI lesions in UA, (2) Determine whether the MRI findings can be translated into an clinical US tool (3) Relate imaging and soluble biomarkers findings to anti-cyclic citrullinated peptide antibody (ACPA) status and prognosis/therapeutic response (4) Develop algorithms for clinical practice.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A prognostic index in systemic sclerosis, integrating biomarkers, autoantibody status and interstitial lung disease severity staging
Funder: Arthritis Research UK

Abstract: Interstitial lung disease associated with systemic sclerosis (SSc-ILD) is a major cause of morbidity and mortality. The course of SSc-ILD is highly variable. Some patients have limited stable lung involvement whereas in others, lung disease progresses inexorably. Our recently established staging system, based on SSc-ILD severity, provides significant prognostic separation between large patient sub-groups, but does not sufficiently address variability in ILD progression in individual patients. There is an unmet need for an integrated staging system in which the severity of disease and the intrinsic progressiveness of disease (captured by biomolecular markers of disease progression and autoantibody status) are reconciled. We plan to assess, in retrospective and prospective SSc-ILD cohorts, biomarkers (KL-6, IL6, CCL18) potentially linked to three pathogenetic pathways and predictive of progression of lung disease in proof of concept studies. The ultimate aim is to develop an integrated risk index, to inform the selective treatment of patients at high risk of progression. A key subsidiary aim is to explore the hypothesis that circulating KL-6 acts to stimulate progression of scleroderma. We plan to examine linkage between serum KL-6 levels and the evolution of skin disease and to evaluate the pro-fibrotic effects of KL-6 on skin and lung fibroblasts.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Validating a new therapeutic target to block inflammation in rheumatoid arthritis
Funder: Arthritis Research UK

Abstract: Rheumatoid arthritis is a chronic inflammatory condition that causes joint destruction. Despite recent advances in new therapies there is still no cure. In this study, the research team will investigate a new drug target which may be able to stop the damaging inflammation seen in rheumatoid arthritis. Rheumatoid arthritis causes severe pain and has a major impact on the quality and length of life of people with the disease. Although recent advances have led to the development of new biologic drugs for rheumatoid arthritis, around 40% of patients do not respond to these therapies and therefore there is still a need for novel therapies to treat this condition. This study builds on previous work by this research team, which revealed that a molecule called NF-κB plays a key genetic role in activating the inflammatory response in rheumatoid arthritis. The researchers believe that it may be possible to block the activity of NF-κB , thereby preventing the damaging inflammation seen in rheumatoid arthritis. If the results of this study suggest that this new drug target has potential , it will present a new, highly selective way of reducing inflammation and pain in rheumatoid arthritis. The integrated approach of this study should bring the drug close to clinical use, offering relief to the chronic inflammation and subsequent joint destruction caused by rheumatoid arthritis.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Haematopoietic stem and progenitor cells as novel therapeutic targets in chronic inflammatory arthritis
Funder: Arthritis Research UK

Abstract: Rheumatoid arthritis (RA) and spondyloarthritis are associated with chronic inflammatory accumulation of macrophages and neutrophils in the joints, which cause progressive cartilage and bone damage. Peripheral numbers of short-lived neutrophils and monocytes/macrophages are highly dependent on the bone marrow (BM) output. However, little is known about the regulation of the upstream haematopoietic stem and progenitor cells (HSPC) during chronic inflammatory diseases and how this could be therapeutically targeted._x000D_ _x000D_ This project will build on my findings in colitis [1] and mouse models of arthritis/spondyloarthritis (attached) showing that HSPCs are severely skewed toward granulocyte-monocyte progenitor (GMP) production in the BM and that highly proliferative and pathogenic GMPs accumulated in the intestine and joints during chronic inflammation._x000D_ _x000D_ Bringing together the fields of immunology and haematopoiesis in order to provide a platform for the identification of novel therapeutic targets in RA and spondyloarthritis, the objectives of this project are to elucidate:_x000D_ _x000D_ 1) How the HSPC compartment adapts to ongoing inflammation and participates in the pathophysiological network in arthritis;_x000D_ _x000D_ 2) What are the key targetable inflammatory pathways promoting dysregulated HSPC activity during arthritis;_x000D_ _x000D_ 3) Whether the regulatory pathways that normally promote balanced haematopoiesis and prevent overreaction of HSPCs to environmental cues are deficient during arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Novel, oral anti-inflammatory compounds for the treatment of rheumatoid arthritis
Funder: Innovate UK

Abstract: Modern Biosciences' anti-inflammatory programme aims to develop a new treatment for rheumatoid arthritis (RA) and related autoimmune disorders. Rheumatoid arthritis affects 1% of the population worldwide. However, up to 40% of patients don’t respond to current treatments. Modern Biosciences' compounds represent a new approach to treating RA that reduces inflammation and also protects bone integrity. The compounds represent an orally-available alternative to the most rapidly growing class of drugs for RA, the injectable ‘biologics’. MBS’ compounds also show good activity in combination with existing treatments and may enhance their efficacy and duration of use. The aim of this project is to identify a candidate compound and take it through the preclinical phase of development before the initiation of clinical trials. Concurrently, the program will evaluate the efficacy of the compounds in other diseases.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Novel age appropriate oral liquid formulation of tacrolimus
Funder: Innovate UK

Abstract: The recognition of the rights of children to have access to safe and effective drugs and the needs of healthcare providers to receive age-appropriate drug information continues to have a major effect on all areas of paediatric pharmaceuticals. In line with this challenge, Proveca’s objective is to develop a new dosage formula of an off patent immunosuppressant which is mainly used following organ transplantation. Children represent a distinct group of organ transplant candidates differing from adults in several important aspects, including pharmacokinetic handling of immunosuppressants and the immune response following organ transplantation. This feasibility project will explore and evaluate the commercial potential and technical feasibility of a licenced paediatric formulation of the immunosuppressant (comprehensive primary and secondary market research, clinical and non-clinical literature reviews, initial experimental studies etc). A development pathway will be identified.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Establishment of a test for MRP levels in childhood arthritis: translating CHARMS to patient benefit
Funder: SPARKS

Abstract: While many new treatments are available for juvenile idiopathic arthritis (JIA), there is currently no evidence-based method for drug stratification. Biomarkers which could predict response to treatment, as well as ways to predict chance of flare if treatment is stopped during remission, are much needed, to streamline medication choices, improve control of arthritis, minimize exposure to toxic drugs, so reducing suffering and disability. Measurement of the protein MRP8/14 has been shown to be valuable for predicting flare after stopping methotrexate (MTX); recent data suggest that S100A12 protein may also function for flare prediction. We have shown that these proteins may also be useful in predicting response to MTX. However, currently no testing of MRP8/14 and S100A12 is available for children with JIA in the UK. In this project we will: • establish/optimise reliable, robust assays for measurement of serum MRP8/14 and S100A12 proteins in JIA • ask if pilot findings about MTX response in CHARMS can be replicated in a validation cohort • investigate use of MRP8/14, S100A12 and CRP to define best methods to predict response to MTX, or flare after stopping MTX • introduce these tests into clinic, investigate if they are feasible and cost effective in assisting the treatment of JIA


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Novel Drug Targets for Treating Rheumatoid Arthritis based on Analysis of Human Genetic Data
Funder: Innovate UK

Abstract: The objectives of this project are to: identify novel drug targets for treating rheumatoid arthritis based on novel proprietary analysis of human DNA data; and develop the business development case for this methodology in drug discovery. PGXIS has developed a novel mathematical method for analysing genetic datasets that allows broad screening of gene-gene interactions. These interactions generate novel insights into the pathways underpinning disease. We have successfully applied this method in both drug discovery and development on behalf of clients. We now propose to apply the method to in-house drug discovery. We plan to analyse the DNA dataset from rheumatoid arthritis cases and controls to identify novel drug targets. These targets will be prioritised and the investor attractiveness of PGXIS's drug discovery programme assessed. Upon completion of this project, PGXIS plans to seek funding to progress the identified drug targets into drug discovery programmes.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Comprehensive analysis of T-cell receptor degeneracy and T-cell crossreactivity
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The 25 million T-cell receptors (TCRs) in the human naïve T-cell pool enable T-cell responses to almost any 'foreign' peptide bound to a 'self' MHC molecule. This complete immune coverage of the array of possible permutations generated from 20 amino acid residues that could bind to the self repertoire of MHC molecules theoretically requires that each TCR must crossreact with over a million different peptides. However, such levels of TCR binding degeneracy encompass the potential for inadvertent recognition of 'self' peptide by TCRs raised against a pathogen; indeed, this is thought to be the root cause of all autoimmunity. Promiscuous TCR recognition can also result in allergic reactions and acute transplant rejection. Despite its obvious importance, there has never been a real attempt to assess TCR degeneracy and T-cell crossreactivity. This paucity of knowledge reflects a lack of methodological tools. Our new technologies and interdisciplinary team now enable the timely fulfilment of this critical research gap. We will use an approach that incorporates T-cell culture/assay, soluble TCR and pMHC manufacture, biophysical/structural analysis of TCR/pMHC interactions, polychromatic flow cytometric dissection of antigen-specific T-cell populations, high throughput direct ex vivo quantitative TCR clonotyping, positional scanning peptide library analysis and bioinformatics to measure TCR degeneracy for the first time. This basic biological research will further our understanding of the very interaction that orchestrates human immunity and will transform the way biologists view T-cell immunity. The study of these pivotal interactions in health will almost certainly be beneficial to understanding their role in disease. This work has obvious and numerous potentials for translation to clinical practice. Our results could influence TCR-based therapies, revolutionize vaccination and illuminate our understanding of autoimmunity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM