NIHRDataInsights/HRCSData huggingface dataset:
Title: Respiratory syncytial virus infection in the elderly: Understanding the effects of aging on the innate immune response
Funder: Wellcome Trust

Abstract: Respiratory infections, such as Respiratory Syncytial Virus (RSV) are a leading cause of morbidity and mortality worldwide, especially among the growing elderly population. Yet the impact of age-related changes in immunity in the lung remains insufficiently studied. In this project, we aim to establish an elderly murine model of RSV infection to studyhow aging alters anti-viral innate immune responses. Old (19-21 months) and young (2-3 months) C57BL/6 mice will be intranasally infected with the human RSV strain A2, and differences ininnate and adaptive immune responses characterised. We hypothesise that there are intrinsic differences in elderly alveolar macrophages, which determine how they respond to RSV and the outcome of infection, and we aim to identify key pathways that are altered in these cellswith age. Using this knowledge, we aim to manipulate the immune response in the elderly to reduce RSV-induced pathology. Finally, through collaboration with clinical colleagues, we will determine whether key mechanisms identified in the elderly mouse model, also differ in human infection in the elderly. Such studies will reveal novel insights into how the immune response to respiratory infection is altered in the elderly, aiding in the future development of new treatments andvaccines.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: CMV TCR Gene Therapy: A Phase I/II Safety, Toxicity and Feasibility Study of Adoptive Immunotherapy in Allo-HSCT
Funder: Medical Research Council

Abstract: The proposed Phase I/II proof of concept pilot study will test the feasibility of generating donor-derived CMV-specific T cells via the ex vivo introduction of a CMV-specific T cell receptor using a GMP grade retroviral vector. It will also determine the safety, toxicity and efficacy of CMV TCR-transduced T cells used for the pre-emptive treatment of CMV reactivation following HLA-matched sibling allogeneic haematopoietic stem cell transplantation (Allo-HSCT). Reactivation of the latent human herpes virus, Cytomegalovirus (CMV) post allogeneic haematopoietic stem cell transplantation (Allo-HSCT) can result in significant morbidity and mortality unless treated promptly. Anti-viral therapy is usually effective, but has serious side effects, such as myelosuppression (Ganciclovir) or nephrotoxicity (Foscarnet). Cellular immunotherapy for CMV has been tested in Phase I/II trials in the UK and Europe. In these trials CMV-specific T cells were isolated from the peripheral blood of CMV seropositive donors and re-infused into recipients following CMV reactivation resulting in sustained anti-viral responses. Transplant recipients with CMV seronegative donors cannot benefit from currently available cellular immunotherapy approaches due to the lack of CMV-specific memory T cells in these donors. At present, there is no reliable strategy to isolate virus specific T cells from uninfected na?ve individuals, as the precursor frequency is low or absent and the in vitro priming of T-cell responses is inefficient. T-cell receptor (TCR) gene transfer offers a strategy to produce antigen-specific T cells independent of precursor frequency and without the need for T-cell priming. We propose that CMV TCR-transduced T cells, generated from CMV-seronegative donors, can generate protective CMV immunity in post-transplant patients.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;6.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION;BLOOD;CANCER AND NEOPLASMS;DISPUTED AETIOLOGY AND OTHER
Title: ISOPLEXIS platform for single cell multiplexed functional proteomics of immune cells
Funder: Wellcome Trust

Abstract: The IsoPlexis IsoLight platform is a unique, highly multiplexed single-cell microchip proteomics technology applicable to both basic and clinical research. Quantitative measurement of secreted proteins associated with a broad range of functional profiles is derived from over 1000 live single cells using intracellular protein detection via high-density antibody barcode arrays. It can precisely dissect the functional heterogeneity ('polyfunctionality') of immune cells with genetically and phenotypically identical signatures and several studies have shown that polyfunctionality determined at the single-cell level can identify critical effector cells associated with durable immunity against infections and cancer. Isoplexis analysis of polyfunctionality in the cell therapy space reveals that phenotypically similar T-cells can have heterogeneous functions and that the 'polyfunctionality index' can provide predictive signatures for toxicity and response to treatment. This state-of-the-art equipment will be housed at the UCL Royal Free Campus and will be used primarily for disease-focused and translational immunology research spanning the disciplines of immunotherapy, autoimmmunity, immunodeficiency, infection (including COVID-19) and cancer. This breakthrough single cell proteomics analysis platform will enable immunology and immunotherapy scientists at UCL to further enhance their understanding of endogenous and engineered human immune cells subsets in the pathophysiology of disease and in the response to treatment.

Lay abstract: Background: The immune system naturally functions to defend the body against infection. In autoimmune diseases (e.g. diabetes), the immune system mistakenly recognises and attacks normal cells. In contrast, where cancer develops, the immune system fails to recognise or attack abnormal cells. Technology which provides a deeper understanding of how immune cells function will be critical to scientists developing better treatments for autoimmune disease and cancer. Approach: This funding proposal is for a novel, state-of-the-art technology (IsoPlexis/IsoLIght) that will allow researchers across UCL to study how the immune system functions in health and disease in a way that has not previously been possible. Expected impact: At a single-cell level and across a wide range of diseases, the Isoplexis/IsoLight will help researchers begin to understand how immune cells can lose normal function, and we expect that these new insights will inform the development of better treatments for infection, autoimmunity and cancer.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION;CANCER AND NEOPLASMS
Title: CLEVER-1 mediates the transmigration of regulatory T cells across hepatic sinusoidal endothelium and promotes resolution of chronic hepatitis.
Funder: Wellcome Trust

Abstract: Liver disease can be caused by a variety of factors including excessive alcohol intake, viral infections and excessive fat within the liver. These conditions are linked by a common pathway which involves white blood cells from our circulation being recruited and accumulating within the liver. White blood cells are important in fighting infection but excessive white blood cell recruitment leads to scarring of the liver and can lead to liver failure and liver cancer. We have identified a mole cule within the liver called CLEVER-1 and have demonstrated that this molecule plays a role in the recruitment of a subpopulation of white blood cells called T regulatory cells (Tregs). T regs have been shown to play an important role in the progression of several liver diseases and the development of liver cancer. In this study we plan to use various models of liver disease to assess the exact role of CLEVER-1 in Treg recruitment and how CLEVER-1 influences the progression of disease in these models. These experiments could identify CLEVER-1 as a therapeutic target to control T regulatory cell recruitment to the liver, which could have implications for a wide range of liver diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION;ORAL AND GASTROINTESTINAL
Title: P2X7 receptor and sepsis-induced acute kidney injury.
Funder: Wellcome Trust

Abstract: Sepsis is when an infection triggers a severe whole-body inflammation. This inflammatory response can frequently progress to failure of multiple organs not involved in the original infection; organs affected include the lung, heart, gut, brain and kidney. When multiple organ failure occurs, the patient requires sophisticated life support in intensive care. In the United States, approximately 700,000 cases of sepsis occur annually, resulting in 210,000 deaths. When acute kidney injury occurs, a t hird of such patients die. Understanding more about the inflammatory response in sepsis may enable us to develop better therapies. I wish to explore a specific mediator of inflammation - the P2X7 receptor. In the kidney, this receptor is absent in health but, in my pilot studies, I have shown that this is strongly present during inflammatory insults such as sepsis. The aim of my project is to further understand the role of this receptor in the kidney during sepsis. This will include the use of a specific blocking agent to see whether this improves kidney function and outcomes. If successful, this may lead the way to clinical trials and, hopefully, an important new treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION;RENAL AND UROGENITAL
Title: Novel immuno-proteomic strategies to develop a polyspecific, non-cold chain liquid snake antivenom with unparalleled sub-Saharan African efficacy
Funder: Medical Research Council

Abstract: To address the sub-Saharan African snakebite therapy deficit, we have devised an innovative 'antivenomic' strategy that maximally exploits the inter- & intra-generic immune cross-reactivity of venom proteins to greatly expand the snake-species efficacy of polyspecific antivenom. We first immobilise a 'base' antivenom, derived from an existing antivenom that is safe & affordable but exhibits inadequate polyspecific efficacy, onto an IgG-affinity column, and venoms from target snakes added. All non-binding proteins are collected and proteomically identified. Those found to be toxic (BLAST search of gene/protein databases) are isolated in sufficient amounts for immunisation (preparative scale chromatography) and mixed with the venoms used to prepare the base antivenom. A new group of sheep is then immunised with the 'venom+supplement immunogen' mixture to rationally, and with minimal additional immunogens, generate antivenom with greatly expanded snake-species efficacy. We will use this approach to generate antivenoms to treat the (i) dermal necrosis & haemotoxic or the (ii) neurotoxic pathology syndromes: thereby covering the effects of envenoming by all medically-important sub-Saharan African snakes. Thus informed, we will next develop a single pan-African antivenom using the first syndromic antivenom as the base to isolate supplement immunogens from all the African snake venoms for 'venom+supplement' immunisation. We will also develop an alternate pan-African antivenom created by mixing IgGs of both syndromic antivenoms in different ratios, and test the ratio exhibiting maximal polyspecific venom protein binding. Serological and murine venom-neutralising efficacy results of the new antivenoms will be assessed against that of the base and existing polyspecific antivenoms. We will also develop protocols enabling non-cold chain storage of liquid antivenom, and to increase antivenom IgG titre & avidity to highly toxic venom but weakly immunogenic proteins.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INJURIES AND ACCIDENTS
Title: A platform for tissue biology to support translational research across musculoskeletal and inflammatory disease
Funder: Versus Arthritis

Abstract: Development of new treatments arising from basic scientific findings generated in the laboratory is extremely challenging and successes are rare. We have identified three major impediments that we believe are modifiable to improve the rate of success. The first of these is suboptimal animal models of disease that recapitulate the human condition. The second is a lack of tissue models in the laboratory that are relevant to the complex tissues in the joint (taking into consideration different cell types and the 3 dimensional structure formed by matrix proteins such as collagen). Thirdly, and most importantly, there is a significant bottleneck that sits between identifying a good target pathway in the laboratory and demonstrating that this really works in living persons who have the disease. That is why, at the Kennedy Institute of Rheumatology, we are proposing the development of a Tissue Biology Platform. This will support a "translational pipeline" to help ensure that only target pathways that have the highest level of evidence are taken through to new treatment development. Specifically, this includes (i) building core scientific expertise to understand complex tissue biology (investing in people to deliver new scientific insights) (ii) developing cutting edge approaches to analyse human diseased tissues at unprecedented detail (iii) developing methods for creating better laboratory 'humanised' tissue models of disease and (iv) supporting staff who will work at the interface between basic science and the clinical trial teams to deliver small scale proof of concept studies in patients (so called Experimental Medicine studies). We believe that this approach will greatly increase the likelihood of finding target pathways that will eventually lead to new treatments in patients. The Kennedy Institute already has significant investment in technology platforms that support cutting edge tissue analysis including tissue imaging and data science (such as single cell transcriptomics). It has fostered the careers of a number of clinician scientists whose disease insights are continually shaped by patient facing activities. The Institute also has unrivalled access to a number of large, highly phenotyped, patient cohorts from which tissue is available for analysis. Together, we believe that this programme will put us in a very strong position to deliver translation to individuals across a wide range of musculoskeletal and inflammatory disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INJURIES AND ACCIDENTS
Title: Psychosis Immune Mechanism Stratified Medicine Study (PIMS)
Funder: Medical Research Council

Abstract: Dopamine receptor blockade remains the sole mechanism of action of antipsychotic drugs since they were discovered over 60 years ago. Despite adequate treatment, psychotic symptoms often persist and poor social and occupational functioning may show little benefit. Low-grade activation of the innate immune system is of increasing interest as a non-dopamine mechanism of pathogenesis and new treatment target. Increased circulating IL-6 and C-reactive protein (CRP) concentrations are present prior to psychosis onset; are related to negative and cognitive symptoms; and may persist in treatment-resistant illness. Although, clinical trials of anti-inflammatory agents in psychosis have yielded mixed results, this may reflect a failure to stratify or select patients who show signs of immune activation. However, the optimal methodology that would identify such a group of patients is not yet clear. The PIMS project will focus on the IL-6/IL-6R pathway and immune markers up and downstream of IL-6 (e.g. IL-1B, TNF-a, CRP) as potential therapeutic targets for schizophrenia. We will use (i) Mendelian randomization to test causality of association of these biomarkers with schizophrenia; and (ii) clinical and epidemiological samples to identify illness stage and symptom dimensions most closely linked with inflammation. This work will inform a randomised experimental medicine study of IL-6 inhibition in selected patients, and test whether they show evidence of a symptomatic, cognitive or a neuroimaging response to a single dose of the anti IL-6 monoclonal antibody, toclizumab, versus placebo over the ensuing month of immune suppression, where we will also carry out deep immuno-phenotyping including functional assays and develop microglia from patients' monocytes to understand the brain relevance of peripheral inflammation. We will use results to refine established murine models to further understand the biology of IL-6 and related immune targets, and to identify new druggable targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;MENTAL HEALTH
Title: From Neurogenesis to Immune Response: How Neural Stem Cells Switch Fate to Communicate with Immune Cells
Funder: Wellcome Trust

Abstract: Humans generate new neurons from stem cells throughout life in the hippocampus; a process called adult hippocampal neurogenesis which is important for learning, memory, and mood regulation. Pro-inflammatory molecules which are produced in response to an activated immune system have a negative effect on adult neurogenesis. However, many open questions remain about how inflammation affects human brain stem cells. We hypothesize that chronic pro-inflammatory stimulation of human brain stem cells can cause them to undergo a switch from neuron-generating to immune-like cells. By stimulating human brain stem cells with pro-inflammatory molecules we will model how adult hippocampal neurogenesis is affected by inflammation. Using this model, we will identify critical molecular mechanisms involved in the stem cell switch from neurogenesis to immune function. Additionally, we will characterize the molecules stem cells produce in a pro-inflammatory environment to communicate back to the immune system and map the effect on their cell fate. Findings from this project can have implications for research into depression, ageing, and Alzheimer’s as these conditions are associated with elevated inflammation and decreased adult neurogenesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;MENTAL HEALTH;NEUROLOGICAL
Title: NRF Fellowship - Do differences in body composition, distribution and physiology of muscle and adipose tissue alter the magnitude of postoperative insulin resistance and inflammation in patients undergoing major surgery?
Funder: CORE

Abstract: Up to 3 million surgical procedures are performed annually in Britain. Although patients may undergo the same operation, some patients go on to develop greater degrees of inflammatory-stress (how ‘sick’ patients get after surgery) than others. This results in certain patients developing marked inflammation and so-called ‘insulin resistance’. Insulin resistance means the body does not respond appropriately to important hormones. This is important as the degree of insulin resistance the body develops determines how rapidly patients recover and whether they develop serious complications after surgery. We do not know why these ‘stress’ responses after major surgery differ so greatly between patients, but think this occurs due to the make-up and function of the body’s muscle and fatty tissues. By studying and understanding these mechanisms we will be able to identify patients at risk of developing marked ‘stress-responses’ and better improve their preparation prior to surgery thereby improving the outcomes of thousands of patients undergoing major surgery. The proposed study will investigate: 1) The roles that different types of muscle and fat in the body (for example muscles/fat in the thigh versus muscles/fat in the abdomen) play in the development of inflammatory-stress and insulin resistance. This is of importance as in the UK patients undergoing surgery are becoming more obese, 2) Identifying better ways of predict the development of inflammatory-stress and insulin resistance in surgical patients. This would allow us to select those patients whom we know will develop marked inflammatory-stress and insulin resistance, and optimize their preparation prior to surgery.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE
Title: CD4 T cell differentiation and regulation in autoimmune diabetes
Funder: Medical Research Council

Abstract: The importance of CD4 T cells in driving autoimmune diabetes has been recognised for some time. According to the original Th1/Th2 paradigm of CD4 T cell differentiation, diabetes was initially attributed to the Th1 subset. However, numerous subsequent observations appear at odds with this conclusion. Recent work has highlighted the potential for additional lineage choices for CD4 T cells, including the capacity to become Th17 cells, follicular helper T (TFH) cells or even Treg. Microarray data obtained using our TCR transgenic model of diabetes suggest the novel possibility that the T cells responsible for this autoimmune disease are TFH cells, the subset that specialises in providing B cell help. The proposed experiments will elucidate the molecular control of TFH cell differentiation and test the hypothesis that these cells play a causal role diabetes. The work will also explore our recent finding that IL-21, the signature cytokine for TFH cells, can counteract Treg suppression, potentially rendering this subset un-suppressible. Collectively our studies will provide new insight into the cellular and molecular pathways that influence CD4 cell differentiation and homeostasis in the context of an autoimmune response. Extending this work directly into human disease, this project will enumerate cells bearing TFH markers in patients with type 1 diabetes (T1D) and ascertain the value of such proteins as biomarkers of disease onset and progression. These studies have the potential to identify new therapeutic targets for the treatment of autoimmune diabetes. Taken together, this proposal constitutes an integrated programme of work that takes advantage of transgenic and gene-deficient mouse strains to generate refined hypotheses for testing in T1D patients. Ongoing iteration between murine and human work will enrich both areas of research and will maximise our progress in understanding the immunological abnormalities underlying autoimmune diabetes.


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