NIHRDataInsights/HRCSData huggingface dataset:
Title: MICA: Immune-Mediated Inflammatory Disease Biobanks in the UK (IMIDBio-UK)
Funder: Medical Research Council

Abstract: Immune-mediated inflammatory diseases (IMIDs) are phenotypically diverse, but share genetic & environmental susceptibility factors & common inflammatory mechanisms. Therapeutics of IMIDs have been revolutionised by specific biologic immune modifiers and immune receptor kinase inhibitors. Discrete responses emerging to given agents across IMIDs suggest the existence of both common and disease restricted pathways. Current immune therapies are prescribed without precision medicine principles. Incomplete response is not uncommon, depending on disease and drug and risk of serious toxicities remain problematic. Collectively these issues, combined with high costs have limited biologic use in the NHS, particularly in rarer IMIDs where disease aetiology and mechanism are not well understood. This is a key area of unmet need. We propose a systems approach to address these challenges that will rely heavily on the presence of large well characterized clinical biobanks informing across IMIDs. This will require significant new bridging infrastructures, including more robust biorepositories that link human tissue to phenotype and outcome. IMID-BIO-UK will address these challenges directly. We will unite several disease biobanks together to create a unique IMID tissue and data repository, unparalleled in scale and scope, to (1) examine disease specific and common endotype concepts across IMIDs beyond those facilitated by existing disease specific cohorts using advanced classification on multi-omic data, and by leveraging clinical cohort databases; (2) focus particularly on blood / tissue biopsy comparisons across IMIDs; (3) integrate multiomic data across tissue compartments including blood and understand the disease specific and common endotype inter-relationship across IMIDs; and (4) use such knowledge to enable rapid repositioning and stratification of therapeutics across IMIDs and enable access for POC studies.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: IMPC: Activation and effector functions of novel antiviral T cell populations in vivo
Funder: Medical Research Council

Abstract: Immunity against infections is classically divided into innate and adaptive responses. However, there are a number of "bridging" cell populations that straddle these two responses, especially at mucosal sites. Amongst these, in humans, MAIT (Mucosa Associated Invariant T) cells represent an abundant subset, have recently emerged as important mediators. These cells are characterised by a restricted TCR usage (Va7.2 and limited beta chains) which allows recognition of bacterial metabolites, but also high level expression of one chain of the IL18 receptor (IL18RAP). This is an important marker but also signalling molecule for the cells as we have recently observed an IL18-dependent TCR-independent activation which allows the MAIT cell pool to respond to viruses. Related T cell types in humans which express high level IL18RAP and co-express the C Type lectin CD161 are also abundant "bridging" populations are mucosal sites and are able to respond similarly to viruses. These 2 observations together massively increase the potential pool of available pro-inflammatory and anti-viral T cells in human disease, but many questions remain about their biology and role in vivo. These questions form the basis for this pump-priming project. We will take advantage of an ideal mouse strain Il18raptm1a(KOMP)Wtsi, which allows both targeting of the specific receptor and reporter tagging. This will allow us to address the following questions in vivo. 1. What is the distribution of the phenotype of IL18RAP expressing cells (including murine MAIT cells) amongst murine T cell subsets in naïve mice. 2. What is the responsiveness of IL18RAP+ cells to relevant viral infections? 3. What is the role of IL18 receptor signaling in the steady state and on the response to infection? This work will establish the model of tracking MAIT cell and related cell types in murine viral infections and generate important data underpinning collaborative project grant applications.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: IMPC Testing dst1 in susceptibility to infection
Funder: Medical Research Council

Abstract: Invasive group A streptococcal (GAS) infection has a mortality of 15-20%, however the highest mortality, 30%, is accounted for by cases of necrotising fasciitis (NF), a rapidly progressive necrotic infection of the subcutaneous tissues and fascia. The condition is very rare but often occurs without any antecedent medical illness or skin injury, consistent with a genetic predisposition. In an effort to identify possible genetic determinants of GAS-associated NF, we carried out a whole exome-sequencing study with a view to identifying rare deleterious variants contributing to susceptibility. We identified six missense variations in a gene called DST, a major component of hemidesmosomes, protein structures that link the epidermis to the dermis by anchoring the lowest cells in the epidermis to the basement membrane. In this project, we will experimentally determine the role played by DST in GAS-associated NF using mice that lack one copy of the gene. We will compare heterozygotes with wildtype littermates of the same sex to determine if heterozygous DST deletion: 1. Increases permeability of the skin to GAS following topical application of GAS in presence or absence of a small skin abrasion; 2. Facilitates spread of GAS to subcutaneous tissues following intradermal injection of GAS; 3. Enables systemic dissemination of GAS from the nasopharynx. These data will have the potential to demonstrate the importance of DST in GAS invasion and will provide a basis for further experimental study of the hemidesmosomes function in susceptibility to lethal human bacterial infection using refined, predominantly mild models of infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: IMPC: Role of ifit2 and stat2 in innate immune defence against arbovirus infection at mosquito bites
Funder: Medical Research Council

Abstract: Innate immune responses are a crucial aspect of anti-viral defences, yet the tissue- and cell-specific basis by which they are coordinated in vivo remains poorly defined. This particularly applies to skin infection by mosquito-borne viruses, a diverse grouping of pathogens that constitute an increasing threat to human health. An important stage, common to all such infections, is the inoculation of virus at mosquito bites. We have recently identified key aspects of skin immune responses to infection at mosquito bites that are important determinants of the subsequent systemic course and clinical outcome of infection. To effectively target pathways at this site therapeutically, we need to better understand them. We now wish to define whether two key innate immune molecules, ifit2 and stat2, are important for anti-viral immune defence in the skin. Preliminary and published data indicates a role for these interferon-induced gene in anti-viral immunity. Here, we will utilise a new mouse model that incorporates the most important aspects of natural infection, including a mosquito bite at the virus inoculation site in the skin. By combining internationally-leading local virology, mosquito biology, and dermatology expertise, this interdisciplinary project will determine how the host coordinates skin innate immune responses at inoculation sites by; - defining the impact of ifit2 and stat2 deficiency on innate immune responses of the skin to infection with virus - determining if ifit2 and stat2 restricts the cell tropism of virus in the skin - determining whether susceptibility to infection with virus at mosquito bites is different in mice that lack ifit2 and stat2 compared to immune-competent mice Thus, we will characterize an important and common aspect of the host response to mosquito-borne virus infection in the skin, and in doing so provide a platform for further studies that will aid development of novel, broadly applicable medicines for mosquito-borne viruses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: IMPC: Role of airway macrophage Btk signalling in pulmonary aspergillosis
Funder: Medical Research Council

Abstract: Pulmonary aspergillosis is a severe mould lung infection that affects 7-8 million people globally. Whilst invasive disease is mainly a consequence of neutropaenia, chronic pulmonary aspergillosis and allergic bronchopulmonary aspergillosis form the major burden of disease, accounting for 7-8 million cases globally. These individuals develop chronic and destructive mucosal infections in the absence of neutropaenia and have defects in macrophage responses to Aspergillus fumigatus challenge. We recently showed that Bruton's tyrposine kinase, a key mediator of B cell responses, is critical for macrophage responses to A. fumigatus. Furthermore, a number of studies have shown that patients with chronic lymphocytic leukaemia receiving the novel Btk inhibitor Ibrutinib are at very high risk of disseminated aspergillosis. Better understanding of the role of Btk in macrophage responses to A. fumigatus in the lung are now required. I will exploit available Cre-Lox technology to delete Btk in CD11c airway macrophages. This will allow me to investigate the importance of macrophage Btk signalling in my murine models of pulmonary aspergillosis. I will undertake a survival analysis comparing CD11c-Btk mice to CD11c-Cre controls after intranasal challenge with 108 A. fumigatus conidia. I will then study control of fungal infection and immune responses by infecting CD11c-Btk mice to CD11c-Cre controls and then performing bronchoalveolar lavage at 24 hours post infection. Cytokine responses, fungal burden and neutrophil influx will be determined. I will exploit innovative precision cut lung slice protocols developed in my laboratory to directly visualise macrophage control of infection and cell death responses, and how this impacts control of infection in the lung, by confocal fluorescence microscopy. These studies will comprehensively define the role of airway macrophage Btk responses in the lung, and form the basis for a follow on grant application.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Elucidation of mechanisms that restrict the activation of Toll-Like Receptors and the IL-1 receptor to prevent inflammatory and autoimmune diseases
Funder: Medical Research Council

Abstract: We have identified novel mechanisms by which the innate immune system is kept in check to prevent the development of inflammatory and autoimmune diseases. We plan to enhance our understanding of these mechanisms, which will facilitate the development of improved ways to diagnose, prevent and treat these conditions. One aspect of our research will be to elucidate how the ABIN family of ubiquitin-binding proteins prevent the development of inflammatory and autoimmune diseases. These studies will build on an exciting discovery that we have made, which may explain why mice-expressing a ubiquitin-binding-defective mutant of ABIN1 develop lupus. We will also elucidate why ubiquitin-binding to ABIN2 is required for the IL-1-dependent induction of cyclo-oxygenase 2 in fibroblasts, following our discovery that this pathway protects mice against intestinal inflammation and DSS-induced colitis. We will also elucidate the function of ABIN3, which is unknown. A further aspect of our research focuses on the SIK subfamily of protein kinases, which function to restrict production of the anti-inflammatory cytokine IL-10 through a mechanism that we have defined. A major aim now is to discover how SIKs promote pro-inflammatory cytokine production and how they operate synergistically with other signalling networks. A further goal is to exploit mouse lines lacking expression and/or catalytic activity of one or more SIK isozymes, which we have made and will develop. In particular, we will investigate whether these mice are protected in several mouse models of inflammatory and autoimmune diseases. We will also investigate the effects of potent and specific small molecule inhibitors of the SIKs in these systems. This is a multidisciplinary research programme that will exploit state-of-the-art techniques such as mass spectrometry, proteomics, signal transduction, immunology, molecular pharmacology, mouse genetics and mouse models of inflammatory and autoimmune disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Regulation of neutrophil functions by cell cycle proteins
Funder: Medical Research Council

Abstract: Neutrophils are essential immune cells that migrate to wounds and sites of infection and engage effector functions such as release of neutrophil extracellular traps (NETs). NETs consist of extruded chromatin released via a cell death pathway called 'NETosis'. NETs are antimicrobial; they bind microbes and prevent them from disseminating but can also be detrimental in inflammatory diseases. Neutrophils are carefully controlled at the levels of activation and localisation, yet in both cases our understanding of mechanisms is incomplete. This project will investigate regulation of NETosis and neutrophil migration with a focus on the role of cell cycle and DNA repair factors. Aim 1 will investigate NET formation and the role of cyclin dependent kinase 6 (CDK6), a cell cycle regulator that is required for NETs. Aim 1a will characterize how CDK6-mediated signalling triggers a checkpoint kinase 1 (CHK1) DNA damage response and leads to NET release. Aim 1b will examine a role for CDK6 in regulating NETs via a metabolic switch to the pentose phosphate pathway. I will use patient samples and a zebrafish in vivo NET model to genetically validate these pathways, as well as phosphoproteomics to identify downstream targets. In Aim 2, I will investigate how DNA repair factors regulate migration of neutrophils in vivo. Specifically, I will examine the role of ataxia telangiectasia mutated (ATM), which I previously showed to be a regulator of neutrophil chemokines. In Aim 2a, I will genetically deplete atm in a zebrafish model that allows tracking of individual neutrophils to wounds and E. coli infections. In Aim 2b, I will test the hypothesis that ATM is a target for bacterial virulence factors. E. coli and other Gram (-) pathogens, produce genotoxins - bacterial molecules that induce DNA damage and activate ATM. I will use the zebrafish model to test the ability of two genotoxins (colibactin and cytolethal distending factor) to modulate neutrophil migration via ATM.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Phase I study of transfer of effector memory T cells (Tem) following allogeneic stem cell transplantation. Short title- Transfer of Tem (ToTem)
Funder: Medical Research Council

Abstract: Following allogeneic stem cell transplantation (allo-SCT), a major risk is graft-versus-host disease (GVHD) that leads to mortality in 10% of patients. Prevention of GVHD relies upon depletion of donor T cells or drugs that block T cell function. However, these methods also increase the risk of life threatening infection and lead to mortality in a further 10-15% of patients. There is an important unmet need for better means of accelerating immune recovery following allo-SCT while avoiding GVHD. Pre-clinical studies have shown that CD62L- effector memory T cells (Tem) improve immune recovery after allo-SCT but do not cause GVHD. We have validated a clinical-scale strategy for selection of donor Tem using a CliniMACs-based depletion of CD62L+ cells and have demonstrated favourable product characteristics compared to methods using CD45RA-based depletion (1). We hypothesise that the early transfer of CD62L- donor Tem will accelerate GVHD-free immune recovery post allo-SCT. Our strategy therefore represents an affordable technology adoptable by any transplant centre. Our aim is to perform a phase I clinical study to determine the safety and maximum tolerated dose (MTD) of Tem following allo-SCT, where grade II-IV acute GVHD is the dose-limiting toxicity (DLT). The results will be used to define a safe Tem dose that can be taken forward into a future phase II efficacy trial. Donor Tem will be given at day 28 following allo-SCT incorporating standard immune prophylaxis against GVHD. We will use a Bayesian continual reassessment model with up to four CD62L- Tem dose levels to determine the MTD. The primary endpoint will be the occurrence of the DLT. Secondary endpoints will include measures of clinical outcome and biological endpoints that measure immune recovery. We are collaborating with other clinical investigators using a CD45RA-based selection method to determine the same biological endpoints, which will inform testing of each strategy in the future.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Induction of human allergen-specific immune regulation following treatment with a combination of Toll-Like Receptor 7 agonist with allergen: an in vit
Funder: Medical Research Council

Abstract: This research study is designed to examine whether stimulation of the Toll-like receptor 7 (TLR7) immune cascade, using selective ligands developed by GSK, can modulate the phenotype of human allergen-specific Th2 immune response and enhance counter-regulatory immune mechanisms, rendering such molecules valid candidates for adjuvants of allergen immunotherapy. Early assessment of the biological activity of the selective TLR7 ligand GSK2245035 has shown preferential induction of IFN-a over TNF-a and a promising pharmacological profile for human use. In this study, the effect of treatment of blood mononuclear cells from grass allergic patients with the TLR7 agonist and grass allergen will be evaluated, in terms of proliferation, cytokine generation and induction of Th cell phenotype. If a shift in the allergen-driven Th2 cytokine production (reduction>50%) is observed, detailed analysis of the mechanisms mediating it will be pursued. In particular the effect of treatment with TLR7 agonist on dendritic cells and monocytes will be examined, as well as how this modulates subsequent new and memory allergen-specific Th cell responses will be analyzed using human APC- T cells co-culture systems. Additionally, the potential generation of functional IL-10 producing regulatory B cells will be explored. In parallel, the effect of the TLR7 agonist on human nasal epithelial cells will be assessed to determine whether it can influence the priming of allergen-specific immune responses. If the results from these studies indicate an effect associated with suppression of allergen-stimulated Th2-like responses, an experimental medicine study, using a nasal allergen challenge model, will be planned to assess whether intranasal administration of GSK224535, together with an adjusted short course of allergen immunotherapy facilitates the induction of allergen desensitisation in patients with grass-pollen allergic rhinitis.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: FAM26F protein: Innate regulator of Type 3 immune responses
Funder: Medical Research Council

Abstract: MFs and DCs are tissue resident cells of the innate immune system. Under homeostatic conditions, they promote tolerance but upon injury or infection they capture microbial antigens to induce a productive effector responses. To elicit productive effector responses, we recently reported that MFs and DCs integrate signals from different classes of membrane receptors (e.g. cytokine receptors and microbial-sensors) which report on the tissue state. To understand how the signal integration in MFs or DCs is translated into the adaptive effector responses, we discovered a poorly studied family of transmembrane proteins FAM26. One member of this family, FAM26F, has recently been linked in genome-wide association studies (GWAS) with ulcerative colitis (UC). We generated FAM26F-deficient mice and found that FAM26F is induced by bacterial and fungal stimuli on APCs, that it regulates induction of inflammatory cytokines associated with UC, and instruction of type 3 (Th17) T cell immune responses. Additionally, we have identified FAM26F-expression deficient humans, permitting direct translation of our results from mice to humans. We propose to use FAM26F-deficient mice and human blood samples to identify FAM26F function and interacting proteins in APCs (using proteomics and high resolution imaging approaches in Aim 1); to characterize mechanism by which FAM26F instructs Th17 responses (using RNASeq in Aim 2); and to understand the role of FAM26F in UC disease progression (using in vivo mouse UC disease models in Aim 3). We have established key collaborations locally, at University of Oxford (Prof. Kessler for proteomics, Prof. Dustin for imaging, Prof. Powrie and Dr. Jostins for biology of UC, Dr. Sansom for RNASeq), which will, with our own expertise in signalling, innate immunity and inflammation, ensure successful completion of the work proposed.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Determining the role of CSF1R-dependent macrophages in of Paneth cells and the intestinal stem cell niche
Funder: Medical Research Council

Abstract: Colony stimulating factor 1 (CSF1R)-CSF1 signalling controls macrophage growth and differentiation. We have revealed a novel role for macrophages in the maintenance of Paneth cells and the intestinal stem cell (ISC) niche. The disturbances to the ISC niche caused by macrophage-depletion after CSF1R-blockade affected the subsequent differentiation of gut epithelial cells, impeding M-cell, but enhanced goblet cell differentiation. Pharmacological CSF1R-blockade has been proposed to modulate certain cancers, and inflammatory, autoimmune and bone diseases. However, our data suggest that modification of the phenotype/abundance of macrophages in the gut after CSF1R-blockade could adversely affect the development of the intestinal epithelium, and the ability of the mucosal immune system to sample gut Ag/pathogens. Paneth cell-dysfunction is also evident in Crohn's disease patients with small intestinal involvement and may be a consequence of inadequate Wnt-ligand stimulation by monocytes. Our data imply that the Paneth cell-dysfunction in CD patients may similarly affect gut epithelial cell differentiation, lumenal Ag sampling and cause intestinal dysbiosis. Our overall aim is to determine the role of macrophages in maintaining Paneth cells and the ISC niche and the consequences of CSF1R-blockade on crypt homeostasis. Our objectives are: 1: To determine the effects of CSF1R-blockade and inducible macrophage-depletion on Paneth cells and the ISC niche throughout the small and large intestines 2: To determine the effects of CSF1R-blockade on gut epithelial cell innate immunity 3: To determine whether macrophage-derived Wnts help maintain Paneth cells and ISC 4: To determine whether R-Spondin1 can protect Paneth cells against the effects of CSF1R-blockade Our data will aid the development of novel therapeutics to counter the effects of CSF1R-blockade on the gut epithelium and to treat intestinal diseases associated with disturbances to crypts and Paneth cells.


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