NIHRDataInsights/HRCSData huggingface dataset:
Title: Natural Killer Cells: Role in the pathogenesis of rheumatoid arthritis major contributors or essential homeostatic modu
Funder: Medical Research Council

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects more than 1% of the world population. Although anti-TNF drugs are the most successful therapy to date, only 70% of patients benefit from this treatment. Therefore, it is imperative we have better understanding of the mechanisms underlying the establishment of chronic inflammation. Whilst the role of cytokines (particularly TNF) in contributing to the pathogenesis of RA has been well documented, the role of T lymphocytes has remained unclear, and the involvement of NK cells not fully understood. NK cells are interesting candidates for therapy since despite their low frequency they are the ?main producers? of interferon gamma at inflammatory sites. Our group has recently shown that surrogates for RA synovial T cells can be generated ex vivo using T lymphocytes from normal peripheral blood stimulated in culture with a cocktail of cytokines (TNF, IL-6 and IL-2). Within this lymphocyte population there is a significant expansion of activated NK cells which, when sorted, are potent effectors of contact-mediated activation of monocytes, macrophages and osteoclasts. In this proposal we wish to translate our current (and limited) knowledge and understanding of cytokine-activated NK cells into the RA-SCID in vivo model of rheumatoid arthritis. We believe this model will allow us to dissect the potential of NK cells to contribute to inflammatory events both in synovial tissue and bone, but also to address their potential not only as inducers of inflammation but also as homeostatic regulators. The RA-SCID model is based upon the engraftment of human synovial tissue (from RA patients undergoing surgery) subcutaneously onto the backs of SCID/beige mice where the human transplant tissue remains viable, becomes vascularised and develops a connection with the mouse vasculature. In addition we will also engraft biopsy fragments of femoral bone to address the potential of NK cells to support osteoblast differentiation and activity as well as NK cell effects on osteoclastogenesis in vivo. Migration of cytokine-activated NK cells to synovial tissue and bone in vivo will be assessed by transfer of labelled cells 4 weeks after transplantation and enumeration of migration of the injected cells to the transplanted tissue using imaging techniques, and removal of biopsies with ex vivo enumeration. This proposal will address (for the first time) the potential of NK cells both to contribute to inflammation but also regulate inflammatory events in an in vivo model relevant to human RA disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Regulation of the adaptive immune response by chemokine scavenging receptors
Funder: Medical Research Council

Abstract: Over the past 20 years much has been learnt about the fundamental roles played by chemokines and their receptors in regulating immune responses. We have been particularly interested in a subfamily of chemokine receptors which are characterised by promiscuous ligand binding and by an apparent inability to signal following ligand binding. Currently there are 4 members of this atypical chemokine receptor family and we have been instrumental in the identification and characterisation of 2 of these namely D6 and CCXCKR. Essentially, both are scavenger receptors, binding and internalising chemokine ligands and targeting them for intracellular degradation. D6 binds all the inflammatory CC chemokines and CCXCKR, in a complementary manner, binds the key homeostatic CC chemokines. These are therefore negative regulators of CC chemokine biology the identification of which has marked a major shift in our understanding of chemokine biology. Our studies on D6 indicate that it plays a strong role in regulating inflammatory responses in vivo. However, our more recent data suggest broader roles for D6 specifically in the context of regulation of adaptive immune responses. The ligand binding profile of CCXCKR immediately implicates it in adaptive immunity and thus we propose that these 2 atypical receptors represent a novel and important axis in the orchestration of the in vivo immune response. We now propose to unify our studies into D6 and CCXCKR under a single programme. We will use shared technologies to carefully investigate their roles in regulating chemokine availability, leukocyte migration and movement and the impact of this on adaptive immune responses. In addition, we have seen that an N terminal fragment of D6 retains the ability to bind chemokines. Given the promiscuity of D6 and its ability to bind all inflammatory CC chemokines, this N terminal peptide may represent a valuable therapeutic agent. We therefore also propose to initiate studies into the usefulness of chemokine scavenger receptor derived peptides as therapeutic agents. In the first instance, this will involve a biochemical analysis of the D6 N-terminal peptide as well as in vivo analyses of its ability to block inflammation in murine models. In addition, we will partner with colleagues at Novartis to develop the therapeutic potential of the D6 N-terminal peptide.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Oral mucosal lamina propria progenitor cells as a novel and preferential source for treatment of Graft Vs Host Disease
Funder: Medical Research Council

Abstract: Mortality due directly to chronic GVHD remains one of the major obstacles in allogeneic haematopoietic stem cell (HSC) transplantation. Research suggests that co-transplantation of mesenchymal stem cells (MSCs) during HSC transplantation results in a significant decrease in acute and chronic GVHD. However, MSC heterogeneity means that trial results are variable and also large cell numbers are required to deliver an immunosuppressive effect which can sometimes initiate an immune response. We have recently demonstrated the existence of a novel, neural crest-derived PC population resident within the lamina propria of the oral mucosa which have a unique immunomodulatory capacity. These clonally-derived oral mucosal lamina propria-progenitor cells (OMLP-PCs) have the ability to lower lymphocyte proliferation back to base levels in the presence of alloantigens, in a contact-independent manner and at ratios as low as 0.001% of OMLP-PCs to allogeneic lymphocytes (levels much lower than for MSCs). This suggests that OMLP-PCs may work via a different mechanism(s) to MSCs and would be potentially more potent/effective than MSCs in the treatment of GVHD. This application will complete the in vitro characterisation of the immunosuppressive potential of OMLP-PCs in direct comparison to MSCs and identify the soluble factors involved in this response. Ultimately this project is aimed at translating our basic research findings into innovative and improved pre-clinical developments for the treatment of GVHD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Human Natural Killer cell-related receptors: diversity, ligands and disease susceptibility.
Funder: Medical Research Council

Abstract: Natural killer (NK) cells have a critical role in protection against viruses and tumours. They express a wide variety of both inhibitory and activating receptors, some of which are expressed on other immune cells. Some NK receptors, such as KIR and some LILR, are highly polymorphic, a feature that is probably driven by resistance to disease. This programme of research will focus on the diversity and functions of human NK receptor genes, adressing three specific aims: 1. We will identify and sequence novel KIR haplotypes and measure the frequency of formation of hybrid KIR genes. 2. We will identify ligands for some key activating receptors, as well as for KIR and adjacent related LILR loci, where these are unknown. We will probe ways in which their counter-receptor binding and functions are affected by polymorphic variation. Our working hypothesis is that is that KIR and LILR interact with MHC molecules complexed with endogenous self peptides, so that a variety of infections may be monitored by upregulation of a small set of proteins in infected cells 3. We will investigate the relationship between receptor variation and expression with disease, by developing a novel rapid KIR typing method.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: University of Edinburgh/MRC Centre for Inflammation Research
Funder: Medical Research Council

Abstract: Inflammatory disorders are a major cause of morbidity and mortality worldwide. Moreover, chronic inflammation invariably leads to tissue and organ fibrosis with adverse functional consequences. There is a critical imperative to identify novel therapeutic targets in inflammation, new approaches to imaging inflammation and fibrosis and to move to translate these developments to clinical applications. The MRC UoE CIR is a multidisciplinary centre in which clinical and non clinical scientists prosecute internationally competitive research to identify targets and deliver translational benefits. Additionally, the Centre is a highly fertile environment for the training of science and medical graduates in inflammation biology. We are requesting renewal of Centre status and funding to continue our highly successful multidisciplinary approach to inflammation research, focussing on three key thematic areas: Immune modulation and regulation of inflammation, Tissue remodelling and regeneration and Imaging inflammation. We request the specific funding of a cohort of 4 year PhD students and two post doctoral fellowships to capacity build in this critical area of medical research.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Molecular analysis of complement activation via the classical pathway
Funder: Medical Research Council

Abstract: The classical pathway of complement activation provides a frontline defence against invading pathogens. It is a central effector of natural protection, one of two current research priorities of the MRC. It neutralises invading cells directly via antibody-dependent and -independent mechanism and elicits a range of cellular responses designed to protect the host and eliminate foreign material, including inflammation, phagocytosis and stimulation of an effective adaptive immune response. Despite its important roles, the mechanisms underlying the activation and regulation of this branch of the immune system are relatively poorly understood. The goal of the proposed work is to understand how molecular interactions control complement activation via C1, the initiating complex of the classical pathway. Biochemical and structural approaches are specifically designed to identify detailed binding and structural information. The results of this study are expected to be of significance to both basic and applied applications. Understanding the fundamental issues of recognition in complement activation has general practical applications in protein-protein interactions and protein engineering and lays the foundations for the development of therapeutic agents designed to prevent complement-mediated host damage for use in the treatment of inflammatory diseases, such as rheumatoid arthritis and in ischemia-reperfusion disorders. As part of this project, short constrained peptide mimics will be developed, synthesized and characterized. These will serve as specific inhibitors of C1q-C1rs interactions, providing a novel set of reagents to dissect the complex biological processes that these proteins mediate. We also plan to use our knowledge of complement interactions to engineer novel specificities into the framework of C1qs, MBLs and ficolins, thereby altering target specificity whilst retaining the ability to activate complement and stimulate the host?s immune system. By targeting bacterial cells and endogenous epitopes associated with disease, these immunologically active reagents will offer a novel approach to tackle disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: GENERATION OF INTRATHYMIC MICROENVIRONMENTS TO ESTABLISH T-CELL TOLERANCE
Funder: Medical Research Council

Abstract: The thymus plays an essential role in supporting the development of T-cells from progenitors arising in the haemopoietic tissues. In addition, because of its importance in shaping the T-cell antigen receptor repertoire for self/non-self discrimination, the thymus is key in both the recognition of invading pathogens and in the avoidance of damaging autoimmune responses. Key to all these processes is the interaction between developing thymocytes and stromal cells constituting the thymic microenvironment. Studies from our laboratory have contributed to the growing understanding that epithelial cells in cortical and medullary micronvironments are key players, and that the functional dichotomy of thymic epithelial cells is reflected in their ability to regulate both positive and negative selection. While the requirements for thymocyte development provided by these stromal cells are becomingly increasingly understood, much less is known of the mechanisms regulating the development and specification of thymic epithelial cells themselves. The central aim of the current proposal is to define these mechanisms by characterizing thymic epithelial progenitors and the molecular processes that control their renewal and lineage specialization. The work will build on two key advances made in our current programme showing that cortical and medullary epithelial cells are derived from a common progenitor (Nature 2006) and that signaling involving TNF-Receptor family of molecules is essential in development of the thymic medulla and self-tolerance (J. Exp. Med. 2007). Specifically, we will analyse the development and persistence of bipotent thymic epithelial progenitors, including investigation of their persistence and regulation of lineage commitment. Together with studies aimed at optimizing a model of thymus transplantation currently in use for the treatment of Di George syndrome, such studies will aid future cell based strategies of thymus regeneration. In addition, by examining the mechanisms regulating formation of the thymic medulla for the regulation of self-tolerance, we will aid in understanding the mechanisms of central tolerance and the avoidance of autoimmunity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Therapeutic Immunoregulation.
Funder: Medical Research Council

Abstract: We discovered, in mice, that short courses of therapy with certain antibodies directed against T-cells could give long-term tolerance to foreign proteins and transplanted tissues, and could restore tolerance in autoimmunity. We have shown that short-term anti-T-cell therapy can also have long-term clinical benefits in multiple sclerosis and in Type I diabetes. The proper harnessing of this ?reprogramming? for clinical application requires that we should understand its mechanisms Mouse models have taught us that, in most cases, tolerance requires the activity of CD4+ regulatory T-cells (Treg) that provide collateral protection to many antigens in the same tissue, and a role for the cytokine TGFbeta. Our capacity to understand how and when Treg operate has been constrained by the lack of a clear targetable cell surface marker. This we have now circumvented by creating a knock-in mouse with a human CD2/CD52 chimeric construct expressed under the control of the Foxp3 gene. In this way all Foxp3-expressing cells can now be identified or ablated with antibodies. Our derivation of a T-cell leukaemia line which can be easily induced to expresss Foxp3, provides a resource to investigate signalling pathways leading to the induction of Foxp3. In this program we hope to: 1) Use our ablative approaches to establish if and when Foxp3+ Treg act in the induction and maintenance of tolerance, linked suppression, and infectious tolerance; 2) Extend our recent discoveries that Treg and TGFbeta turn on cascades of enzymes concerned with catabolism of essential amino acids, and the generation of adenosine and, in conjunction with effects on the mTOR pathway, convert other T-cells to regulatory function. 3) Interrogate the role of the tissue microenvironment in promoting the function and further generation of Treg. 4) Utilise this information to develop improved strategies to harness regulatory mechanisms to control unwanted inflammatory and immune damage.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: CRAC channel-dependent calcium microdomains and mast cell function in health and disease
Funder: Medical Research Council

Abstract: Allergies in the U.K. have reached epidemic proportions, with conservative estimates indicating that almost one in three people are affected. In addition to the direct costs (~ 1 billion pounds each year is spent on treating allergies), the socio-economic costs are substantial with around 13 million working days lost each year and academic performance of allergy sufferers in schools is considerably lower than their non-affected peers. Mast cells are intimately involved in the initiation and maintenance of allergic responses. Allergen-induced activation of mast cells opens store-operated CRAC channels in the plasma membrane and the subsequent Ca2+ microdomains leads to exocytosis of histamine-containing granules, synthesis and secretion of pro-inflammatory lipid-derived signals, and increased expression of genes coding for chemokines and cytokines. The molecular composition and properties of the CRAC channel in human mast cells and how calcium microdomains (accompanying CRAC channel opening) activate spatially and temporally distinct responses is unknown. Using state-of-the-art methods, we will compare CRAC channels properties and subsequent exocytosis in mast cells from normal individuals with patients suffering from severe allergic rhinitis to establish how the response pattern has changed in the diseased state. Collectively, this programme should lead to the identification of new therapeutic targets for drugs aimed at combating this growing health crisis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The supramolecular dynamics of human immune cell recognition and communication
Funder: Medical Research Council

Abstract: The key focus of my research over recent years has been the successful combination of addressing important problems in cell biology and immunology with novel and state-of-the-art photonics technology. Our imaging studies have helped establish an emerging new paradigm that interactions between immune cell receptors, kinases and adaptors are at least in part controlled by the dynamics of supramolecular assemblies. Thus, immune cell recognition and signalling is governed by transient interactions between heterogeneous clusters of proteins, a substantially different concept from the linear cascade of individual protein-protein interactions depicted in textbooks. Thus, the new challenge presented here is to assess the heterogeneity and single-molecule level organisation of protein clusters and understand how this influences signal integration and downstream effecter functions. Addressing this major gap in NK cell biology, and immune cell biology in general, necessitates the application of new super-resolution imaging techniques. Thus, we will engineer a range of specific cellular interactions and apply super-resolved imaging techniques, including STORM and PALM, which will permit step changes in the speed, resolution and level of quantification. We will compare the dynamic organisation of the NK cell synapse when the overall signalling is tipped towards inhibition or activation. Also, we will use photocleavable peptides able to trigger NK cell inhibition upon activation to determine the timing of NK cell signal integration in relation to interactions and dynamics of NK cell microclusters. In addition, we have recently presented evidence that intercellular membrane nanotubes connecting a wide variety of immune cells can aid functions such as NK cell-mediated cytotoxicity and can be exploited by pathogens, such as for the spread of HIV-1 between T cells. Thus, membrane nanotubes represent a new research area which may be important across many biological systems both in health and disease. Using a combination of state-of-the-art and novel imaging techniques, we now propose to compare and contrast the molecular structure of nanotubes between different cell types and test specific functions for nanotubes including aiding cell-mediated cytotoxicity and communication via sub-micronscale nanotube synapses. Finally, we will also establish a new line of research to investigate intercellular transfer of RNA. We will determine which types of RNA transfer and probe the mechanism for RNA transfer. We will test for specific functional consequences of RNA transfer, including that it could be the basis for a novel viral evasion strategy and/or a new way by which cells communicate with each other.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM