NIHRDataInsights/HRCSData huggingface dataset:
Title: Regulation of Intestinal Immune Responses by the Atypical Chemokine Receptor CCRL1.
Funder: Medical Research Council

Abstract: Leukocyte migration directed by CCR7 and CCR9 plays a central role in regulating intestinal immunity and tolerance, and drugs targeting CCR9 are being developed to treat inflammatory bowel diseases. The atypical chemokine receptor CCRL1 (CCX-CKR) binds the same chemokines as CCR7 and CCR9, but seems to act as a chemokine scavenger. We have found that CCRL1 deficient mice are completely refractory to the induction of oral tolerance to protein antigen, and show enhanced responses to mucosal immunisation. This is associated with a striking reduction in plasmacytoid dendritic cells (pDC) in mesenteric lymph nodes (MLN) arising from a stromal defect in these mice. Lymphatic endothelial cells (LEC) appear to be the main CCRL1-expressing cells in the intestine and MLN, raising unexplored questions about LEC regulation of pDC trafficking and function. Moreover, CCRL1 might also control conventional DC (cDC) in the intestine, as these cells have to traverse LEC barriers using CCR7 during their migration from the lamina propria into lymph, and from lymph into MLN. Therefore, we hypothesise that, by governing homeostatic chemokine abundance and/or distribution at LEC surfaces, CCRL1 controls DC in trans to regulate the intestinal immune system. We will test this hypothesis by answering the following questions: (i) Does CCRL1 loss affect cDC in the intestinal immune system? (ii) How and why are pDC in MLN altered by CCRL1 deficiency? (iii) How does CCRL1 influence antigen presentation and T cell differentiation in the MLN? (iv) What role do pDC play in CCRL1-dependent intestinal immune regulation? (v) Are mucosal defects in CCRL1 deficient mice due to loss of chemokine control by stromal cells? By providing new perspectives on pDC function, chemokine control of intestinal DC, the regulation of chemokine networks, and immunoregulation by LEC, this work could identify CCRL1 as a novel target for treating inflammatory bowel disease or enhancing responses to mucosal vaccination.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;ORAL AND GASTROINTESTINAL
Title: Outcomes of Periodontal Therapy in Rheumatoid Arthritis (OPERA)
Funder: Department of Health (England)

Abstract: Background RA is a chronic immune-mediated inflammatory disease associated with significant morbidity and, primarily due to cardiovascular disease, increased mortality. More than 500,000 people in England suffer from rheumatoid arthritis, with approximately 26,000 new cases being diagnosed every year. Chronic periodontitis is arguably the most prevalent chronic inflammatory disease of humans and several lines of evidence indicate that periodontitis may be a causal risk factor for RA. Effective and safe treatments for chronic periodontitis exist and a small number of preliminary studies have indicated that successful treatment of periodontitis may benefit patients with RA in terms of RA disease activity. Aims Our mid-term goal is to evaluate the effectiveness, cost-effectiveness and safety of intensive periodontal therapy and maintenance administered by dental hygienists in an intermediate/secondary care setting to reduce disease activity of rheumatoid arthritis. The specific aims of this pilot study are to (i) evaluate the feasibility of a randomised controlled clinical trial in terms of patient recruitment, intervention delivery, compliance, and outcome assessment as well as acceptability of intervention and study procedures to patients and (ii) to collect pilot data on effect size and variability of various clinical and laboratory outcome measures relevant to rheumatoid arthritis. Plan of Investigation We plan to conduct a randomized parallel-group randomized controlled clinical pilot trial of the short-term effects of non-surgical periodontal therapy on RA disease parameters. Patients with established rheumatoid arthritis and moderate to severe chronic periodontitis will be eligible for inclusion. The intervention group will receive intensive non-surgical periodontal therapy with rigorous periodontal maintenance; the control group will receive oral hygiene instructions for the duration of the trial, and full therapy at the end of the study. Patients will be followed for 6 months. Outcome measures include clinical and serological markers of RA and disease activity, and general and oral health related quality of life. Potential Impact RA is a common disease associated with significant morbidity and cost to the NHS. Treatment of more than 500,000 patients with RA results in annual healthcare costs to NHS of around £560 million in England alone. Total costs of rheumatoid arthritis to the UK economy are estimated to be as high as £3.8 to £4.8 billion a year. In addition, RA is associated with increased mortality due to cardiovascular disease. Periodontitis is a common chronic infection that can be treated effectively and relatively inexpensively. Hence, if periodontal treatment was effective in reducing RA disease activity it would constitute an inexpensive and safe non-pharmacological means of improving outcomes in RA, resulting in direct patient benefit and potential savings to the NHS and the economy.


Research activity codes: 6.4 SURGERY
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;ORAL AND GASTROINTESTINAL
Title: An investigation into the defective termination and resolution of acute inflammation in ulcerative colitis
Funder: Wellcome Trust

Abstract: Acute inflammation is a protective response against infection or trauma. Usually it is self-limiting, but may persist and in doing so cause chronic disease. Although a considerable amount is understood about the mechanisms and molecules involved in its initiation, far less is known about processes involved in its termination and the healing reaction. This project will be directed at identifying the mechanisms of disrupted inflammation resolution in the chronic inflammatory bowel disease, ulc erative colitis (UC). I will use a model of acute inflammation (called skin windows) in patients to establish where UC inflammatory responses diverge from those of healthy individuals. The relevance of abnormalities identified in these studies will be confirmed in subsequent experiments on the bowel. The skin window studies will then guide investigations into specific processes known to be involved in inflammation termination and resolution, to understand the molecular causes responsible for their dysfunction. I will also investigate a specific pathway (TLR4/TRIF) that is abnormally activated in a subset of white blood cells (macrophages) in UC. Molecular abnormalities identified in these experiments will allow exploration of novel drug targets in UC. The same molecules and systems may also prove important for a variety of other chronic inflammatory diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;ORAL AND GASTROINTESTINAL
Title: Unravelling clinical and biochemical aspects of CFHR5
Funder: Medical Research Council

Abstract: Disordered regulation of complement contributes to a range of diseases including cardiovascular disease, age related macular degeneration and glomerulonephritis. During my MRC Clinical Research Training Fellowship I identified a novel monogenic disease, Complement Factor H-Related 5 (CFHR5) nephropathy, which causes complement dysregulation in the kidney. The disease is associated with a mutation in the CFHR5 gene (a homologue of CFH) and is a common cause of renal failure among Cypriots. As well as defining a clinical cohort with a unified disease pathophysiology, these findings implicate CFHR5 as an important regulator of complement. The mechanism by which the mutation causes disease is not understood. CFHR5: structure and functional relationships I will measure the affinity of CFHR5 proteins for other components of the complement system (including Factor I, C5 and C3) and initiate crystal structure determinations of the mutant and wild-type CFHR5 proteins. This will establish the major biochemical properties of CFHR5, using the mutant protein to highlight those properties with significance in CFHR5 nephropathy. Frequency of CFHR5 nephropathy I have identified over 100 patients with CFHR5 nephropathy in London and Cyprus, and will establish a registry of patients with this and other CFHR5 abnormalities to identify prognostic markers which correlate with outcomes. The high prevalence of CFHR5 nephropathy in Cypriots is unexplained. While this could result from genetic drift, enhanced complement activation may protect against an infectious organism present in Cyprus, selecting for the mutation. I will measure the ability of patient and control serum to opsonise microorganisms, using recombinant proteins to determine if any differences result from the CFHR5 mutation. CFHR5 in other diseases Complement deposition is common in glomerulonephritides, including mesangiocapillary glomerulonephritis, IgA nephropathy and lupus nephritis. I will develop an assay for circulating CFHR5 to determine its utility as a biomarker for glomerular inflammation in these diseases. In addition, I will administer the CFHR5 proteins to mice with experimentally induced glomerulonephritis to determine whether human CFHR5 can ameliorate renal injury. Other CFHR5 mutations I have collected DNA samples from patients and families with unexplained hereditary glomerulonephritis. I will use linkage exclusion mapping and molecular genetic techniques to determine whether other mutations in CFHR5 cause kidney disease among this population. Treatment of CFHR5 nephropathy I will set up an experimental study to test whether eculizumab (a clinically licensed monoclonal antibody against C5) influences the disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RENAL AND UROGENITAL
Title: Can differences in Th1 IFNg-to-IL-10 cytokine switching mediated by CD46 predict functional outcome after renal transplantation?
Funder: Medical Research Council

Abstract: Chronic rejection (CR) is the biggest cause of renal allograft failure. Surprisingly little is known about the cell-mediated interactions that underpin CR. Differences in "Interferon gamma (IFNg)-to-IL-10 switching" and contraction of Th1 pathway have been demonstrated in autoimmune disease; I will test the hypothesis that patients with CR have functional differences in antigen-specific Th1 "IFNg-to-IL-10 switching" and that these differences associate with graft function. In HLA-typed healthy 'cones' we will demonstrate that CMV gpB antigen-specific indirect ELISPOT reactivity is associated with differences in Th1 IFNg-to-IL-10 switching using flow cytometric cytokine assay. I will attempt to identify antigen-specificity in these assays. The microenvironment matters: autocrine secretion of IL-1B mediated by NLRP3, via C5a with C5aR1 engagement is known to suppress IL-10 production; whereas engagement with C5aR2 favours IL-10 switching. We will investigate whether signalling through C5aR1/C5aR2 correlates with IFNg or IL-10 production in our viral antigen model system. The relevance of these findings will be assessed, by analysing patient samples from the 'OuTSMART' clinical trial to correlate Th1 switching variation with graft outcome. The involvement of CTSL, C3, NLRP3, Il-1B and signalling through C5aRs will be confirmed in HLA-stimulated CD4+ T cells, addressing whether persistent IFNg production can be modified by manipulation of these molecular pathways. Finally, if sequencing of C5aRs demonstrates that polymorphisms are associated with IFNg-to-IL-10 switching in CMV antigen stimulated cones; we aim to sequence C5aRs in transplant samples and look for an association between (donor antigen-specific) C5aR-polymorphism and graft outcome. The project is expected to shed new light on the molecular basis of anti-donor T cell activity and suggest potential avenues for future therapeutic manipulation to preserve organ allograft function.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RENAL AND UROGENITAL
Title: MICA: Investigating the role of myeloperoxidase as a key mediator of renal damage in crescentic glomerulonephritis and reno-cardiac disease
Funder: Medical Research Council

Abstract: Crescentic glomerulonephritis (CGN) represents a severe form of kidney injury that can occur in the context of various diseases. Common to many forms of CGN is abnormal or excessive glomerular neutrophil and monocyte activation with evidence for release of proteases and neutrophil extracellular traps (NETs). We and others have shown a significant extracellular deposition of leukocyte myeloperoxidase (MPO) in various forms of CGN and evidence for augmented circulating levels of MPO in patients with CGN. Despite its importance in innate immunity, MPO deficiency does not result in a significant clinical phenotype. We propose to investigate if MPO is a critical mediator of glomerular damage and could represent a novel therapeutic target in CGN, using preclinical models of CGN and the novel MPO inhibitor AZM198. We will test whether susceptibility to CGN is in part related to MPO deposition and whether MPO inhibitors can prevent neutrophil activation and NET formation, found in CGN. Finally, chronic autoimmune conditions leading to CGN often result in accelerated cardiovascular disease and MPO has been shown to play a critical role in atherosclerosis, so we will investigate the impact of inflammation, induced by ANCA associated CGN, on atheroma and the effect of MPO inhibition.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RENAL AND UROGENITAL
Title: MICA: Investigating ATP regulation and P2X7 blockade in acute renal injury and its long-term complications
Funder: Medical Research Council

Abstract: ATP signalling through the P2X7 receptor may mediate renal inflammation in AAV, causing acute kidney injury, and accelerated arterial calcification, complicating CKD. ATP levels are normally tightly regulated and a fine balance exists between extracellular ATP production and degradation, mediated by CD39 and CD73 found on numerous cell types but particularly regulatory T-cells. Recent work has highlighted genetic variations in the ATP-degrading ectonucleotidases as significant risk factors for severe vascular calcification. We wish to define the interactions between ATP and its P2X7 receptor and to investigate the potential for abrogating these harmful responses using the AZ P2X7 receptor inhibitor. We will make use of two pre-clinical rat models, one of acute renal vasculitis and glomerulonephritis the other of arterial calcification and progressive renal disease, to mimic the clinical scenarios of acute and chronic kidney disease. We will also investigate mechanisms through which ATP signalling via P2X7 mediates inflammation and arterial calcification using our established in vitro models of aortic ring calcification and granuloma formation. In addition, we will examine expression, genetic and functional differences in CD39, CD73 and P2X7 between healthy subjects and patients with renal inflammation secondary to autoimmune AAV as well as CKD patients with varying degrees of arterial calcification. The data generated should help define the key role played by ATP-P2X7 signalling in inflammatory kidney disease and arterial calcification, allow us to identify and stratify high risk patients and provide a means of personalising treatment using a novel treatment strategy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;RENAL AND UROGENITAL
Title: Starting a family when you have inflammatory arthritis: can a co-production approach to creating pre-conception health improve the sustainability of NHS services?
Funder: Health and Care Research Wales (Welsh Government)

Abstract: One in ten women who have recently given birth in the UK report having a long-term limiting illness (LTLI). While most of these women will have healthy pregnancies, there are some increased risks, such as a higher rate of early births (10.9% with LLTI having premature births vs. 6.8% without), lower breastfeeding rates (25.6% of babies breastfeeding beyond three months vs. 33.4%), and increased chances of children developing a LTLI by age seven years (12% vs. 6.2%). Inflammatory arthritis (including rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitisis) is one of the conditions that affect women of childbearing age. Women face important and complicated decisions, such as whether they want children, when, options for contraception, and whether to change/stop medications before trying to get pregnant. Women with inflammatory arthritis currently struggle to get enough information and support with these decisions. This project aims to find out whether a co-production approach to healthcare for women with inflammatory arthritis who are considering pregnancy could improve the sustainability of NHS services. In co-producing health, women would become more empowered and active in making decisions about their care. The researcher will work in partnership with a Stakeholders Group (women, their partners, and health professionals) to co-develop an intervention. The intervention will focus on helping women and their health professionals co-create health by sharing decisions, taking into account women’s wishes and desires in relation to starting (or enlarging) a family. Interviews with 30 women, partners, and health professionals will inform what should be included in the intervention package and how it should be provided (to whom, when and by what format). The intervention will be piloted with 20 women who are using local Rheumatology services. Feedback will be gathered on how the intervention worked, whether it was useful, and how it could be rolled out.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Neuroinflammation in endometriosis: macrophages behaving badly?
Funder: Medical Research Council

Abstract: Endometriosis is a common chronic inflammatory disorder characterised by debilitating pelvic pain and hypersensitivity. Treatments are limited to hormonal suppression or surgical excision of lesions and symptoms commonly recur. There is an un-met clinical need for new strategies to treat endometriosis-associated pain. I believe that the pain is a consequence of neuroinflammation; the growth of new nerves and their activation by inflammatory mediators within the lesion. Endometriosis-associated macrophages are critical players in the pathophysiology of endometriosis. I have generated evidence indicating that isolated human M2 or 'regenerative' macrophages exposed to oestrogen to mimic the microenvironment of human endometriosis lesions both enhance neurogenesis and increase the expression of inflammatory cytokines. However, it is unknown how endometriosis-associated macrophages contribute to neurogenesis, neuroinflammation and pain in vivo. The objectives of this project are: 1. To use the macrophage depletion mouse, Cd11b-DTR to determine how macrophages present in the shed endometrium contribute to the establishment of lesions using a mouse model of 'menstruation' and a novel mouse model of endometriosis 2. To use the Cd11b-DTR mouse to determine how macrophages influence neurogenesis and neuroinflammation in established lesions in a mouse model of endometriosis. 3. To interrogate the effect of macrophage-derived factors identified in (2) on nerve function using in vitro models of sensory neurons. 4. To determine the role of macrophages in endometriosis-associated pain and hypersensitivity using behavioural monitoring in mice and to explore how inhibition of macrophage-derived factors ameliorate endometriosis-associated pain. I am confident the work will generate novel data leading to high impact publications, significant advances in the field and the identification of novel targets with translational value for the treatment of endometriosis-associated pain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Defining the role of monocytes and monocyte-derived macrophages in the pathophysiology of endometriosis to accelerate clinical translation
Funder: Medical Research Council

Abstract: Endometriosis is an enigmatic, incurable condition with insufficient therapeutic options. There is also no non-invasive diagnostic option for peritoneal endometriosis (most common form) and visualization of lesions at laparoscopy remains the gold-standard. Monocytes and macrophages are intimately linked with the pathophysiology of endometriosis. In a mouse model of induced endometriosis, we have demonstrated diverse populations of macrophages that differentially impact lesion development, with a protective role for monocyte-derived large peritoneal macrophages (LpM). Thus, if monocyte-derived LpM are protective against the development of endometriosis, we postulate that a defect in monocytes / monocyte-derived macrophage function will be evident in women with endometriosis. We will use single cell discovery and in vitro functional assays to phenotype and characterize peritoneal monocytes and macrophages and peripheral blood monocytes in women with endometriosis. Our objectives are: 1. To use single cell (sc)RNA-seq and in vitro functional assays to define the phenotypic and functional adaptations of monocytes and monocyte-derived macrophages isolated from the peritoneal cavity of women with endometriosis. 2. To identify a unique expression signature on peripheral blood monocytes from women with endometriosis using scRNA-seq and evaluation for diagnostic potential in independent cohorts.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The placental glucocorticoid barrier: regulation by corticotropin-releasing hormone (CRH) during inflammation.
Funder: Wellcome Trust

Abstract: During human pregnancy, the placenta expresses complex machinery to dynamically control (and limit) fetal exposure to glucocorticoids. Since this system is sensitive to the actions of inflammatory molecules, we hypothesize that in pregnancies associated with inflammatory disorders, this placental glucocorticoid (GC) barrier might be specifically targeted and that placentally-derived corticotropin-releasing hormone (CRH) might play a key role in adaptation to dysregulated inflammatory responses. The aim of this project is to elucidate the role of CRH in the regulation of placental signalling machinery controlling GC bioactivity in normal placenta and how this system responds to states of inflammatory disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;REPRODUCTIVE HEALTH AND CHILDBIRTH