NIHRDataInsights/HRCSData huggingface dataset:
Title: Top Jabs - Improving vaccination responses in older adults
Funder: Medical Research Council

Abstract: Older adults are more susceptible to bacterial and viral infections than young people and the national vaccination programmes against influenza and Streptococcus pneumonia are the primary preventive measure aimed at reducing incidence of these infections. However, the decline in immune function in old age reduces the ability of older individuals to mount successful vaccination responses, with less than half of over 65 year olds producing a protective response to influenza. With age both the quantity and quality of antibody produced is reduced, which will reduce the efficacy of vaccination in older adults. Many older adults are therefore not benefitting from the protection provided by vaccination. There is an urgent need to understand why the vaccination response is compromised in old age and to develop interventions to improve vaccination responses in elders. We plan to address several aspects of the immune response to vaccination in older animals and humans to determine why there is a failure to develop good humoral immune responses in older adults. T cell memory and B cell differentiation are directed by adult lymphoid tissue inducer (LTi) cells. We will test if and how their reduced function impacts on reduced antibody responses in old age. In addition, immune complexes have been used as adjuvants in old mice, and we will study how antigen-masking changes selection and affinity maturation of B lymphocytes in lymphoid tissues in older animals. Crucially, we will test whether antigen-masking can be used as an efficient and novel vaccine adjuvant in older animals. Age related hormonal and metabolic changes also contribute to reduced immune responses. The study will test whether insulin sensitivity is related to vaccination responses, and will test in a small pilot study in animals whether a pharmacological intervention (metformin treatment) can improve vaccine response. Finally, a simple behavioural intervention will be used to modulate efficiency of vaccination responses: Our preliminary data show that diurnal variations in older adults lead to changes in the quality of humoral vaccine responses. We will repeat this in a larger randomised trial and test whether diurnal changes in responsiveness are due to variations in stress hormones or cytokines. If proved effective, this observation will lead to a simple intervention by manipulating the timing of immunization to improve the response to vaccination in older adults.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Towards a cure for early rheumatoid arthritis
Funder: Medical Research Council

Abstract: New cases of inflammatory polyarthritis (IP) may either resolve spontaneously or evolve into rheumatoid arthritis (RA). Early diagnosis and prompt therapy with tight control have been shown, in clinical trials, to alter the long-term course of early RA towards a more benign outcome by limiting structural damage and long term disability. Nonetheless, clinical remission is only achieved in a minority of subjects with early RA, and sustained drug-free remission remains a rare event. There is therefore a major unmet need to identify the characteristics of those individuals most likely to achieve clinical remission either spontaneously or in response to specific drug therapies so that new and existing therapies can be targeted to the right patient populations. Thus, identification of accurate predictors of spontaneous resolution, mild disease in early RA, and treatment response would prevent patients being exposed unnecessarily to potentially toxic therapies and permit stratification of patient populations in clinical trial and clinic settings. There is also a need to accurately define clinical and biological outcomes that unambiguously reflect drug efficacy. The aims of this research are to establish reproducible and clinically relevant criteria for ?biological remission states? that incorporate imaging and immune phenotypes, to establish the key predictors of clinical remission in early IP and RA patients and to identify individuals at high risk of developing RA in whom prognostic factors for remission and ongoing active disease can be validated. To achieve these objectives, we will first assemble an inventory of relevant UK clinical cohorts and clinical trials. We will then collate anonymised patient-level data from RA patients randomised, in controlled clinical trials, to receive (a) placebo or (b) active drug, and use this information to establish the characteristics, frequency, duration and clinical consequences of spontaneous and drug-induced clinical remission. A new, UK-wide longitudinal observational study of early RA patients will be established, in which patients will receive intensive treatment according to NICE guidelines. Clinical, imaging and immunological assessments, including novel in vivo assays of resolution, will be undertaken, and the data used to identify further biological predictors and descriptors of the remission state. Finally, we will undertake a feasibility study using existing EPIC/NOAR and UK Biobank cohorts to characterise individuals captured prior to RA onset based on demographic, genotypic and autoantibody profiles. This will provide novel insights into the very earliest phase of the disease and provide a framework for disease prevention strategies in the future.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: An Immunological Toolkit for Clinical Application
Funder: Medical Research Council

Abstract: Current management of rheumatoid arthritis (RA) is based upon measurement of inflammation and tissue damage. However these are downstream consequences of immune dysregulation, and sub-optimal guides for managing patients and designing disease-modifying drugs. Our aim is to identify the key immune abnormalities that define RA and to develop an immunological toolkit: a set of functional and flow cytometry-based assays to study and monitor the dysfunctional immune system. A UK-wide collaboration of academic and industrial scientists will develop the toolkit, using regular discussions and workshops. Although current theory suggests that key immune abnormalities in RA should reside within T- or B- lymphocytes, lessons from other diseases suggest a discovery approach to be most appropriate, encompassing deep immunophenotyping of major peripheral blood immune and inflammatory cell subsets. Therefore in phase I purified CD4+ and CD8+ T-cells, B-cells, monocytes, NK cells and neutrophils will undergo: multiparameter flow cytometry for cell surface phenotype, intracellular cytokine and lineage transcription factor expression, and signalling pathways; transcriptional analysis using Affymetrix U219 microarrays; and small RNA sequencing. A well-defined subset (n=30) will subsequently undergo ultra-deep RNA sequencing, providing a complete picture of the RA transcriptome. We will study three sets of individuals: 30 healthy controls during an evolving vaccination response; 200 established RA patients, stratified for disease activity and disease duration; and 30 RA patients receiving abatacept (costimulation blockade). Hypothesis-generating phase I will provide a detailed signature of cells and pathways that characterise the RA immune system, and inform the design of customised, low-density array(s) (LDA), alongside the initial development of relevant in vitro immune function assays. In phase II these will be applied to 100 patients with recent onset inflammatory arthritis, sampled longitudinally, alongside a refined panel of flow cytometry protocols. Signals that are consistent between phases I and II will lead to further refinement of the in vitro assays ready for phase III, which encompasses proof-of-concept studies with novel therapeutic compounds, provided by industrial partners. Here the final immune toolkit will be ?road tested?, providing a secondary outcome measure that predicts conventional efficacy parameters. Success in this challenging programme will provide a novel portfolio of immune function assays, potentially applicable to RA but also other immunopathologies. Their widespread adoption and application across diseases will reinforce the successful image of UK translational immunological research. Intellectual property generated by the work will be protected for future exploitation as appropriate.


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
Title: FINE MAPPING OF REGULATORY GENETIC VARIATION INVOLVING COMMON AUTOIMMUNE DISEASE ASSOCIATED HAPLOTYPES IN THE HUMAN MHC
Funder: Medical Research Council

Abstract: There is a significant inherited component in susceptibility to autoimmune disease with the most striking and robust genetic associations involving sequence variation in the major histocompatibility complex (MHC) on chromosome 6p21. However fine mapping these disease associations and resolving specific functional variants has proved a significant roadblock in the field. This is made more challenging at this locus due to the remarkably polymorphic nature of the MHC and extensive coinheritance or linkage disequilibrium between variants. There is also a need for a more integrated approach to the resolution of genetic determinants of common disease, recognising the importance of epigenetic mechanisms and context-specific regulation of gene expression. Here we propose to define functionally important genetic variants modulating gene expression for common autoimmune disease associated haplotypes spanning the MHC. We know that there is significant heritable variation in gene expression involving the MHC. Our data from lymphoblastoid cell lines HLA-homozygous for HLA-A1-B8-Cw7-dr3, A3-B7-Cw7-dr15 and A26-B18-Cw5-dr3-DQ2 demonstrates that haplotype-specific differences in gene expression are common and often involve differences in alternative splicing. We propose to extend this analysis to carry out transcript profiling using RNA-seq for B lymphocytes and monocytes from HLA-homozygous healthy volunteers selected by genotype for eight common autoimmune disease associated haplotypes. These haplotypes were completely re-sequenced as part of the MHC Haplotype Project and are strongly implicated in autoimmune diseases including type I diabetes, systemic lupus erythematosus and multiple sclerosis. We will then confirm haplotype-specific differences and define specific local (likely cis-acting) or distant (likely trans-acting) variants by expression quantitative trait mapping combined with allele-specific transcript quantification. Specific regulatory variants will be characterised in the context of the local regulatory landscape based on chromatin profiling together with reporter gene analysis, assays of protein-DNA interactions, small interfering RNAs and assays to define allele-specific expression of alternatively spliced isoforms Our analysis of transcription will be complimented by epigenetic profiling to define haplotype-specific differences in DNA methylation involving the MHC. This work will provide unique insights into the functional basis of observed associations with autoimmune disease for commonly occurring haplotypes in European populations. This has significant translational importance in advancing our understanding of disease pathogenesis and defining patients at risk of disease or most significantly benefiting from specific therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: MiRNA-155 regulates B cell function through its target PU.1
Funder: Medical Research Council

Abstract: MiRNAs (miRNAs) are increasingly being recognised as major regulators of gene expression. Their expression provides an additional level of regulation beyond transcriptional control, permitting more rapid establishment of stable gene expression patterns. It is now apparent that miRNAs regulate many aspects of the immune system, including adaptive immune responses. During the course of adaptive immune responses B lymphocytes must respond rapidly to antigenic stimulation by initiating complex changes in gene expression that allow differentiation into effector and memory cells. These events lead to the production of high affinity antibodies and development of lasting immunological protection which underpins effective vaccination. The present work aims to test for a functional relation between a particular miRNA, miR-155, and one of its targets, PU.1. My previous work has implicated miR-155 for optimal adaptive immune responses of B cells in a cell-autonomous manner. I have shown that miR-155 is required for optimal immunoglobulin class switch recombination (CSR) and identified the transcription factor PU.1 as miR-155 direct target. In this project, I present some unpublished data establishing a causal relation of miR-155 and its target PU.1 for regulating CSR. I propose to follow up those observations by performing a thorough analysis of the significance of those observations in the context of adaptive immunity in vivo and to understand the molecular mechanisms by which miR-155 through its target PU.1 regulates the generation of switched B cells. The prospect of targeting miRNAs for therapeutic use is exciting and could open up new complementary treatments for cancer, inflammation or effective vaccination. There is already an antagonist for a miRNA in clinical trials for the treatment of hepatitis C. The proposed work will contribute to uncover the regulatory network regulated by miR-155 through its target PU.1 which may be exploited for effective vaccination.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The Regulatory Importance of SOCS molecules in Th2 Immune Responses and Disease
Funder: Medical Research Council

Abstract: Allergies are systemic disorders that manifest as atopic dermatitis (AD), food allergy and allergic rhinitis (AR), all characterised by elevated IgE levels and peripheral eosinophilia. The aetiology of allergy involves complex interactions between local and systemic immune responses, but Th2-cell differentiation and expression of Th2-type cytokines are important in disease development. Significantly higher levels of IL-4 and IL-13 lead to isotype switching to IgE synthesis. Polarisation of different CD4+ T-helper cell subsets is driven by cytokines. The suppressors of cytokine signalling (SOCS) family control cytokine signalling and the contribution of SOCS (1, 2 and 3) to the development of T helper 2 (Th2) allergic disease is the focus of this proposal. We have found that SOCS2-/- CD4+ T cells have markedly enhanced Th2 differentiation and that SOCS2-/- mice have elevated type 2 cytokine production after helminth antigen challenge. Moreover, in in vivo models, of atopic dermatitis SOCS2-/- mice had significantly elevated specific IgE, eosinophilia, type 2 responses and inflammatory pathology relative to WT mice. This preliminary work supports the hypothesis that SOCS2 null CD4+ T cells are prone to develop into Th2 thus these mice are prone to allergy. Are key goals are to 1) Examine T-helper polarization & signalling in SOCS2-/- T cells 2) Explore if Th2 responses directly linked to SOCS dysregulation in CD4+ T cells? 3) Measure SOCS expression seen in T-cells from patients with allergy to determine if this is also true in patients. This work will have important implications in the understanding of molecular mechanisms involved in the predisposition to atopic disease


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of MicroRNA142 in Immunoregulation and Transplantation
Funder: Medical Research Council

Abstract: Background MicroRNA (miRNA) are a class of short, non-coding RNA which regulate post-transcriptional gene expression and play a pivotal role in innate and adaptive immune responses. Our laboratory focuses on the regulatory gene networks involved in CD4+ T cell differentiation and function. We have recently shown that the master regulatory T cell transcription factors T-bet and GATA3 bind to the promoter of microRNA (miR)142. In order to determine the function of miR142 in T cell lineage determination we have created novel constitutive and conditional knockout mice for this locus. These mice are viable and display a profound defect in their regulatory T cell (Treg) compartment. A major goal in transplantation is the induction of tolerance; indefinite allograft survival without the need for life-long immunosuppression. Tregs are critical mediators of tolerance and express the transcription factor FoxP3. Co-expression of T-bet or GATA3 is important for Treg function in specific immune responses. However, the molecular mechanisms that regulate Treg function and stability are, to a large extent, unknown. Aims and Objectives The aim of the project will be to test the hypothesis that miR142 is important for Treg function by demonstrating that its altered expression has significant effects on Tregs and results in an immunological phenotype that affects outcomes in transplantation. Design and Methodology 1. In vitro experiments will involve suppression assays on miR142 global and conditional (FoxP3) knock-out mice, testing the hypothesis that these mice have reduced Treg function. Parallel in vitro experiments will investigate the effects of miR142 over-expression in human cells. 2. In vivo experiments will utilise mouse models of transplantation to test the hypothesis that miR142 is implicated in allograft rejection, by comparing graft survival in wild type and knockout mice (constitutive and conditional). 3. Finally, the utility of miR142 as a biomarker of renal allograft status will be tested in human renal transplant recipients by looking at miR142 expression in peripheral blood before, during and after episodes of rejection. Scientific and Medical Opportunities This project will provide insight into the molecular mechanisms by which the immune system responds to allogenic stimuli. On a translational level, it could contribute to the development of a novel biomarker for the prediction of immunological tolerance. Indeed, there is emerging evidence that miR142 expression in human renal allograft biopsies predicts acute rejection. Furthermore, microRNAs are a potential target for therapeutic modulation with modified antisense oligonucleotides, furthering the search for novel specific immunosuppressants.


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
Title: The molecular and cellular basis of complement-mediated T helper 1 (TH1) differentiation and regulation
Funder: Medical Research Council

Abstract: Control of IFN-gamma-secreting CD4+ TH1 effector T cells is vital for the prevention of immunopathologies during and after infection and unwanted responses against self or innocuous antigens. IL-10 is a key cytokine mediating negative control of TH1 responses. Although IL-10 is produced by several cell types and, thus, many cells can ?extrinsically? suppress TH1 responses, a novel concept now suggests that the major TH1 suppression pathway may be represented by ?intrinsic? regulation: A negative feedback loop working via the timely coinduction of IL-10 in addition to IFN-gamma within TH1 cells. Although the importance of IFN-gamma to IL-10 switching is acknowledged, the molecular pathways regulating these two cytokines in TH1 cells are undefined. We identified the complement regulator CD46 as key receptor in regulating IFN-gamma and IL-10 production in TH1 cells (Cardone et. al, Nature Immunology, 2010). We demonstrated that CD46 not only drives IFN-gamma production and effector function of human TH1 cells but also induces the switch to IL-10 secretion and into the regulatory phase in an IL-2-dependent fashion: In the presence of low IL-2 CD46 induces almost exclusively IFN-gamma+ effector TH1 cells while high environmental IL-2 then switches these cells from an IFN-gamma+/IL-10+ intermediate finally into IL-10+ T cells, with both of the latter populations being suppressive. Importantly, we showed that this CD46-mediated switch is defective in rheumatoid arthritis (RA) patients: T cells from these patients lack the IL-10+ cell subpopulation, produce up to 20 times more IFN-gamma compared to those from healthy individuals and never enter the regulatory phase. Thus, we hypothesize that CD46-transduced signals play a vital role in the induction and resolution of human TH1 responses and that disturbance in CD46 signals is associated with RA. This application aims now at delineating the molecular signals regulating IFN-gamma/IL-10 switching in human TH1 cells. We propose that each of the CD46/IL-2-mediated sequential phases in the TH1 cell ?life cycle? (IFN-gamma+, the IFN-gamma+/IL-10+ and IL-10+) are defined by the expression of specific genes and miRNAs as well as distinct changes in the chromatin environment. We will identify those changes and generate a comprehensive transcriptomic signature of each of the TH1 induction and regulation phases present in T cells from healthy donors (in comparison with T cells from RA patients). This ?molecular landscape? will then provide an experimental framework to identify single proteins and pathways required for IFN-gamma/IL-10 switching, and to uncover the defect(s) in TH1 regulation in RA.


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