NIHRDataInsights/HRCSData huggingface dataset:
Title: Imaging neoangiogenesis in rheumatoid arthritis
Funder: Versus Arthritis

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis which can result in progressive joint damage and diability. In RA the inflamed synovial membrane is characterised by abundant new vessel formation which correlates with the clinical degree of synovitis. Imaging techniques which visualise synovial inflammation and vascularity, specifically magnetic resonance imaging (MRI) and power Doppler ultrasound (PDUS), have better sensitivity for joint inflammation over routine clinical examination and X-rays, enhance clinical predicition of progression to RA in early inflammatory arthritis and predict outcomes and reponse to treatment in patients with active RA. Furthermore, they can predict short-term reponse to therapy, for instance in patients being treated with biologic agents. However, both MRI and PDUS are expensive and time consuming and in practice only imaging of limited number of joints is possible. There is therefore an unmet need for an accessible imaging technique which can image multiple inflamed joints at the whole-body level and which correlates with current gold-standard methodology.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Immune-complex mimetics (ICMs): an adjuvant free approach to controlling the major diseases for which no vaccines are available
Funder: Wellcome Trust

Abstract: For many serious diseases, including malaria, there are currently no effective vaccines. Many vaccines under development also require co-administration with adjuvants that often have ill-defined mechanisms of action, are difficult to manufacture, are often unstable, and can have toxic side effects in humans. Richard Pleass, from the Liverpool School of Tropical Medicine, has developed, patented, and licensed a platform technology that is able to cross-link immune receptors, found on antigen presenting cells, with high specificity and avidity. This Pathfinder Award will allow Richard and his team to determine if this technology can be repurposed for the delivery of antigens directly to dendritic cells for use in vaccines. It is hoped that this approach will dispense with the need for adjuvants accompanying vaccines, by mimicking the natural immune-potentiating effects of immune-complexes. Although immune-complex mimetics may be suitable for any disease for which vaccines are required, the Award willl use model antigens from malaria to determine if this technology is feasible for vaccines. If this proof-of-principle Award works with the malaria model antigens, the technology should also work for any ligand for which multimerisation may endow useful therapeutic or diagnostic properties.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Experimental Medicine INitiative to Explore New Therapies (EMINENT) network training programme
Funder: Medical Research Council

Abstract: Experimental medicine lies at the core of MRC translational research strategy, translating basic scientific discovery into benefits for human health. Delivering effective experimental medicine requires the involvement of clinicians and scientists with bespoke skills sets; integrating mechanistic disease insight with experience of drug development and clinical trial design, for which a critical skills gap has been identified by the MRC. A key objective of EMINENT is to address this skills gap with the specific aim to ‘Develop a cohort of excellence in experimental medicine, through targeted training for early career scientists and fellows’. This cohort of clinical and non-clinical scientists, will be unique within the UK, and consist of individuals who will have the aptitude, training, experience and skill set to allow them to work between academia and the pharmaceutical industry to deliver high quality, integrated experimental medicine studies and early phase clinical trials. To capitalize on the opportunity created by EMINENT, the MRC, GSK and five partnership Universities (UCL, Glasgow, Cambridge, Newcastle and Imperial), together with the NIHR, wish to establish a formal EMINENT Training Programme in which all EMINENT-funded technical, post-doctoral and clinical research staff, will be expected to participate. This includes the additional five NIHR-BRC and GSK funded Clinical Research Fellowship posts, which will be established at Cambridge, UCL, Imperial, Newcastle and (with EMINENT support) Glasgow University.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining macrophage heterogeneity in psoriatic arthritis to inform future therapeutic opportunities
Funder: Medical Research Council

Abstract: "Recent studies in our group have delineated macrophage heterogeneity within healthy human synovial tissue macrophages (STM) and identified dynamic phenotypic changes in STM subpopulations in both the active inflammatory and resolution states that are associated with rheumatoid arthritis (RA). Furthermore, it is now apparent that the within these novel STM subpopulations, some possess immune-homeostatic functions that govern and sustain disease remission whilst others may drive disease flare. In comparison, macrophage heterogeneity within the skin and synovium of Psoriatic Arthritis (PsA) is currently unknown. Studies are urgently required to define macrophage set-point in PsA, as this will provide new understanding of treatment resistance and remission of PsA. Thus, the aims of this PhD programme are: (1) to establish the heterogeneity of synovial tissue macrophages in PsA and how this differs from the healthy synovium and the synovitis of patients with RA, we will use cite-scRNAseq to analyse myeloid cells from synovial tissue biopsies from treatment-naive PsA patients and compare with equivalent data sets already established from healthy synovium and RA synovium (2) to establish the heterogeneity of Psoriasis (PS) and PsA skin tissue macrophages and how this differ from the healthy skin using cite-scRNAseq on healthy, naïve to treatment PsA and PsA skin biopsies. (3) to dissect the STM subpopulation distribution and molecular pathways that differentiate PsA patients responding to current treatments with those who are treatment resistant, we will compare the synovial tissue macrophage subpopulations and their molecular signature in PsA patients resistant to anti-TNF or anti IL-17 treatments, and PsA patients responding to these biologics. (4) to characterise the cell communications between distinct synovial tissue and skin macrophage clusters with other tissue cells in driving pathology or resolution, we will computationally predict the interactions using whole skin and synovial tissue scRNAseq and validate/map them in structures of the skin and the synovium using spatial transcriptomics and/or hyperion. Altogether, this PhD programme will provide a comprehensive analysis of the functional capacity of human skin and synovial tissue macrophages in PsA patients with both persistent pathologies and sustained disease remission. Our data will define the presence and function of different human tissue macrophage subpopulations and inform future biomarker and therapeutic target opportunities in PsA. "


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Microbiome - Mouse genetic models of barrier immunity dysfunction: Role of the microbiome in modifying disease phenotype
Funder: Medical Research Council

Abstract: Maladaptation between host and microbiome at barrier surfaces, leading to local and systemic inflammation underlies a number of genetic diseases, for example, cystic fibrosis (CF) and inflammatory bowel disease (IBD). There is an unmet need to understand the mechanisms by which the microbiome contributes to development of these diseases so that underlying pathways can be targeted for therapeutic gain. More broadly, there is a need to better understand and control for the impact of the microbiome on host phenotype in order to refine use of mouse models and improve reproducibility in mouse genetics research. The 'Microbiome and Barrier Function' cluster will bring together diverse expertise to establish a pipeline for creating and manipulating mouse models of human genetic diseases involving epithelial barrier immunobiology and the microbiome. Initial focus will be on three monogenic human disease models, representing IBD (Syk), CF (Cftr), and combined immunodeficiency syndrome (Arpc1b). The pipeline will subsequently be extended to other monogenic disease models that impact different layers of epithelial barrier biology. The cluster will develop cutting-edge laboratory, gnotobiotic, and bioinformatic techniques, including rederivation of strains under germ-free conditions, humanized and novel synthetic microbial communities, models of infection and challenge to barrier surfaces, and in-depth genomic and metabolomic characterization of the host and microbiome. The outcome will be identification of causative roles for the microbiome in exemplary disease models, which will then be mapped back to relevant human disease cohorts. Through collaboration with the Mary Lyon Centre, the cluster will establish new standards and capacity for mouse microbiome research. These resources will be made available to academic and industry partners across the UK who wish to understand and control for the microbiome in their own research.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Host-pathogen biology
Funder: Medical Research Council

Abstract: The human TRIM family comprise 70 members and are implicated in diverse cellular processes including cell proliferation, differentiation, development, oncogenesis and apoptosis. Our research program is designed to determine the mechanisms of function and dysfunction of two groups of TRIM proteins that are particularly crucial to human health the antiviral and disease-associated TRIMs.||Antiviral TRIMs operate intracellularly to restrict viral replication. The mechanism by which these TRIMs target virus and prevent replication is not known. To understand these mechanisms and how viral specificity is encoded, we are determining the detailed three-dimensional interactions that occur between the multiple domains of TRIM proteins, viral proteins and the host cell machinery. In particular we are interested in why human TRIM5alpha, which in primates limits SIV replication, is defective against HIV.||Disease-associated TRIMs are those in which disruption of function has been shown to mediate disease. Dysfunction of these TRIM proteins can increase susceptibility to disease (e.g. TRIM20/pyrin), cause congenital defects (e.g. TRIM18/mid1) or mediate autoimmunity (e.g. TRIM21/Ro52). We are using a combined molecular and cellular approach to determine both the mechanisms of function of these TRIMs and their pathophysiology.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Dendritic cells and initiation of immune responses
Funder: Medical Research Council

Abstract: Dendritic cells (DCs) play a key role in initiation of T cell-mediated immune responses against pathogens and tumours, as well as in maintenance of peripheral tolerance. DC deficiencies in animal models and in patients result in an inability to control infections, malignancies, and auto-immune diseases. Considering that the outcome of the interaction between a DC and a naïve T cell can have dramatically different consequences (immunity vs tolerance), DC functions must be tightly controlled. It is the quality and quantity of the following three signals that determines whether DCs are tolerogenic or immunogenic, and whether antigen-specific T cells will proliferate into effectors or undergo anergy/deletion: signal 1 - MHC class I-bound peptides, identical to those present in target cells (recognised by T cell receptor, TCR); signal 2 - cell surface molecules that act as stimulatory or inhibitory co-receptors, and signal 3 - chemokines and cytokines that modulate T cell proliferation and differentiation. Our overall goal is to understand in molecular detail the transcriptional programmes, intracellular signalling events, and protein trafficking pathways that control generation of these three signals and thereby the outcome of the T cell-mediated immune responses. Specifically, we focus on two questions: (i) What are the molecular mechanisms of antigen presentation in DCs? All nucleated cells display on the cell surface MHC class I molecules loaded with peptides derived from proteasomal degradation of endogenous proteins. This pathway of antigen presentation can also be used by virally infected DCs to stimulate virus-specific T cells. However, many viruses suppress antigen presentation and not all relevant antigens are expressed in DCs (e.g. neoepitopes from cancer cells). Therefore, immune responses also rely on DC’s unique capacity to load their MHC I molecules with peptides derived from exogenous proteins (a process termed cross-presentation). Underpinning the molecular mechanisms involved is the pathway is the central goal of this research programme. (ii) How is cross-presentation regulated during tolerogenic and immunogenic responses? During infection, recognition of pathogen-associated molecular patterns (PAMPs) by innate receptors initiates transcriptional programmes that lead to production of cytokines, chemokines and co-stimulatory molecules turning DCs strongly immunogenic. PAMPs also mediate reorganisation of subcellular trafficking pathways in order to enhance the efficiency of antigen presentation on MHC class I, and promote DC migration to lymph nodes. Molecular details of intracellular pathways engaged during initiation of tolerance or anti-tumour immunity (i.e. in the absence of PAMPs) are poorly understood. Our goal is to identify endogenous mediators required for generation of signals 1, 2 and 3 during tolerogenic and anti-tumour immune responses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding and mediating the toxicity of CAR-T cell therapy
Funder: Medical Research Council

Abstract: Chimeric antigen receptor- (CAR-) T cells, have generated considerable excitement over the last ten years, owing to unprecedented single agent anti-tumour activity. Whilst highly effective, CAR-T cells have well-documented and often serious toxicities. Two of the most common are cytokine release syndrome and CAR-T cell related encephalopathy syndrome. Management of these complications frequently involves intensive care unit support and treatment with expensive drugs. Acute toxicity can be fatal, whilst the long-term effects of these syndromes and the therapeutic interventions they necessitate are not yet understood. Reducing the impact of cytokine release syndrome and neurotoxicity is thus of vital importance. There are several inter-related challenges for understanding CAR-T cell toxicity. These include the on-target nature of the toxicity; the unpredictable nature of development and severity of toxicities in individuals; the heterogeneity of immune systems between individuals; and the heterogeneity of immune cells within individuals. Single-cell RNA-Seq (scRNA-Seq) has the potential to address these challenges. Recent developments from proteomics work in our laboratory can enhance scRNA-Seq technology, allowing the accurate prediction of cell surface marker expression in an unbiased fashion. This, in turn, will allow us to characterize patients’ immune cells in “real time” and to isolate populations of cells for mechanistic study. Our aims for this program are to understand the following: 1) Which cell subtypes and signalling pathways contribute to the release of cytokines in the setting of CAR-T cell therapy? 2) How can we predict which patients will experience clinically significant cytokine release syndrome and/or neurotoxicity during treatment with CAR-T cells? 3) How can we mitigate against cytokine-associated toxicity during CAR-T cell treatment? We will work with samples from patients undergoing CAR-T cell therapy at Addenbrookes, taken prior to lymphodepletion and post-CAR-T infusion. We will derive scRNA-Seq and proteomic data from plasma membrane profiling to identify subpopulations of immune cells and define immunophenotypic markers. We will use these markers to perform fluorescence-activated cell sorting to isolate functionally homogeneous populations of immune cells. These cells will be used in various in vitro assays to study signalling, cytokine release, and cell-cell interactions. The immunophenotyping markers will also be used to characterize patients’ immune microenvironment prior to CAR-T cell treatment and machine learning will be employed to detect patients at risk of toxicity. We will use the results of these initial studies to propose interventions in CAR-T cell therapy (e.g. individualized dosing, prophylactic tociluzumab, small molecule inhibitors of specific signalling pathways) that will be tested in vivo and may be used to inform early phase clinical trials.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining the mechanism of toxicity from loss of immune checkpoints
Funder: Medical Research Council

Abstract: The majority of the toxicity associated with therapeutic targeting of the immune system is caused by inappropriate activation of adaptive immunity. Immune toxicity is an increasing problem because of (1) the exponential increase in immune targets, (2) the heterogeneous effects of immune-targeting on a target human population— both efficacy (response rate) and toxicity (severity and organ site) are unpredictable for any individual subject. This program aims to improve this by defining critical factors necessary for efficacious and toxic adaptive immune activation. Our approach is distinctive as we have unique access to an animal model system that allows us to track the fate, persistence, and effector function of individual adaptive immune lymphocytes responding to diverse antigenic triggers. With this, we can test hypotheses and identify critical factors necessary for an adaptive immune response that leads to effector cells within a specific tissue site. We also have access to samples and data from cancer immunotherapy treated and rare-disease patients with genetic loss of a therapy relevant immune pathway. To focus on validating this approach we have generated a hypothesis regarding the toxicity from targeting the autoimmune disease target IL-6R and the cancer immunotherapy immune target CTLA-4. IL-6R targeting toxicity: Our work defining human IL-6R deficiency demonstrates that these patients, as are tocilizumab (anti-IL-6R) treated patients are at risk from the atopic disease. We have postulated that this is because the loss of this checkpoint biases T helper cells to clonally expand and differentiate into an atopic phenotype due to dysregulated cytokine signalling. Suggesting the atopic toxicity of IL-6R targeting requires the production of cytokines and T cell activation. CTLA-4 targeting toxicity: CTLA-4 targeting leads to adaptive immune dependent inflammation in diverse tissue sites, including the lung, gut, and liver. Our prior work on the effects of CTLA-4 loss suggests that this checkpoint provides a cell-intrinsic restraint on clonal expansion and differentiation of self-responsive adaptive immune lymphocytes. In tissues where there is non-specific sterile inflammation, this would lead to self-antigen triggered immune inflammation. These hypotheses are best tested in preclinical models in which stochastic-environmental T cell activation and cytokine production is controlled and therefore can be experimentally delivered. However, we will collect and assay samples from patients with either genetic or therapeutic targeting loss of the same checkpoint, seeking to demonstrate that similar mechanisms apply in people. Assessing the success of this approach will have relevance for toxicity studies on a wide-range of immune targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Risk factors for genital inflammation among women at high risk of HIV in Uganda: a mixed-method, longitudinal analysis
Funder: Medical Research Council

Abstract: This project will identify the behavioural and biological risk factors for genital inflammation by conducting a longitudinal, mixed-method study with women at high risk of HIV infection, bringing together the violence/mental health and molecular biology/immunology fields of research. Genital inflammation is causally associated with HIV acquisition but the cause of genital inflammation is often unclear; behavioural risk factors have not been investigated. There are physiological and immunological reasons to suggest that violence experience and heavy alcohol use could increase HIV acquisition risk by increasing genital inflammation, potentially through a mental health pathway, but there have been no epidemiological studies to investigate this. We need to know (i) what the behavioural and biological risk factors for genital inflammation are and the pathways between these risk factors; (ii) if genital inflammation changes over time, according to exposure to and treatment of these risk factors; and (iii) the prevalence, severity and frequency of women's experience of violence, mental health morbidity and genital inflammation. This proposal will bring together different fields of analysis to answer these research questions. The proposed project will conduct a longitudinal, mixed-method study with 750 women at high risk of HIV infection in Kamapala, Uganda and examine all known and potential risk factors for genital inflammation, as well as potential confounders. Longitudinal qualitative research conducted with 25 women at two time-points, will be used to inform the conceptual pathway and the epidemiological analyses. The study findings will be used to design interventions to address women's multiple needs. This may include, for example, targeted clinical (e.g. anti-inflammatories; HIV Pre-exposure Prophylaxis (PreP)), behavioural (e.g. alcohol prevention) and empowerment (e.g. violence prevention) components, to complement existing HIV services.


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