NIHRDataInsights/HRCSData huggingface dataset:
Title: Construction of a miniaturized human lymph node model as an alternative to the Local Lymph Node Assay
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Every year, thousands of animals are used for testing the immunogenicity and allergenicity of many chemicals that are used in making healthcare, cosmetic, domestic and industrial products (e.g.paint&solvents). Currently the 'goldstandard' assay used by industry to predict allergenic potential of new chemicals is called the Local Lymph Node Assay (LLNA). In this assay, animals (mainly mice or guinea pigs) are exposed to chemicals for a few days followed by injection of a radioactive tracer, subsequent euthanasia and excision of the lymphnodes for the investigation of T cell proliferation. Whilst it is difficult to determine the exact number of animals used for LLNA, there are reports indicating use of nearly 10,000 animals per year for this purpose in the USA with an expected similar number used in EU. Therefore, not only because of our obligation to minimise animal suffering but also due to a recognized gap in terms of the biological relevance of animal models to human, there is a pressing need to develop human based alternatives to such animal experiments. Lymphnodes are miniorgans that are scattered around the body and house different types of immune cells. The Paracortex of a lymphnode is where professional antigen presenting cells (e.g.dendriticcells) interact with white blood cells called T cells. Dendritic cells (DC) act as sentinels of the immune system and are usually located in mucosal surfaces and barrier tissues (e.g.skin) where they can sample the environment and capture any foreign material (microbial products or chemicals). Subsequent to this, they travel to a local lymph node where they interact with T lymphocytes, trigger T cell activation and initiate an immune response. In this project we have brought together scientists in the fields of immunology, tissue engineering, biomaterials and microfludics from the Universities of Nottingham and Harvard as well as an industrial partner with extensive experience in chemical testing and propose to develop a 3D tissue engineered model of the human lymph node in the laboratory. We will simulate many features of the human lymph node (e.g.cellular and extracellular matrix composition, cell orientation and flow) and design the model such that we can study cell interaction, activation and differentiation. Once established, this model would provide an invaluable tool for testing immunogenicity/allergenicity of new drug leads and chemicals and could reduce and possibly replace the LLNA.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Using C. elegans to produce proteins from parasitic nematodes for research and therapeutic use
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Parasitic nematodes have evolved methods to evade the human immune system, including the secretion of proteins that suppress host inflammatory responses. We have made significant progress in understanding the properties of one such protein, ES-62, which is produced by the rodent filarial nematode Acanthocheilonema viteae. ES-62 has been shown to be protective in mouse models of inflammatory diseases such as rheumatoid arthritis and asthma, suggesting potential therapeutic use. This progress has been possible because we can maintain A. viteae in gerbils and ticks. However, we need to sacrifice hundreds of lab rodents each year for this work, and it is expensive and time consuming. Furthermore, many more animals would have to be sacrificed to produce enough ES-62 for a clinical trial. We propose to replace lab rodents by producing ES-62 in the free-living nematode Caenorhabditis elegans. This nematode can be grown in the laboratory in large amounts simply by culturing with a bacterial food source. Moreover, C. elegans can modify proteins with phosphorylcholine (PC)-N-glycan structures as found on ES-62. This modification is important for the immunomodulatory activity of ES-62. There are several established methods to make transgenics in C. elegans to direct the expression of recombinant protein. Others have used C. elegans to produce proteins from parasitic nematodes in a limited manner before but we have developed a novel strategy to improve production and purification of recombinant proteins. The resulting proteins will be tested for PC modification and immunomodulatory activity. Our proposal is not only designed to directly replace lab animals in the manufacture of ES-62 but also to show that quantities large enough for therapeutic and commercial purposes can be manufactured. Furthermore, it can be applied to producing immunosuppressive proteins from other nematode species including human parasites, therefore potentially offering further substantial benefits.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Enabling people with the oral allergy syndrome to eat fresh fruit
Funder: Department of Health (England)

Abstract: Background Birch pollen allergy causes early season hayfever and asthma. Between 30-50% of patients with birch-pollen allergy experience oropharyngeal itching, irritation and swelling on eating certain fresh fruits and vegetables (oral allergy syndrome - OAS). This is due to a cross-reaction between birch pollen and proteins in fruit of the Rosaceae family (apples, pears, peaches, plums etc). Patients report that this interferes with lifestyle and prevents them from consuming fruits and vegetables. Desensitising the patient to birch pollen might abolish or attenuate OAS. Thus far, the scientific evidence is very limited: three studies have given contradictory results, but none were adequately powered or controlled. Aims To conduct a double-blind placebo-controlled study of birch pollen immunotherapy (BP-SIT) in patients with early season hay fever who experience fruit-related symptoms To evaluate the efficacy of BP-SIT to reduce symptoms of itching, irritation and local swelling on eating apples (graduated challenge protocol). To assess clinical responses by recording hay fever symptoms and confirm responsiveness by objective challenge conjunctival test with birch pollen at baseline and after one and two years of BP-SIT. Plan of Investigation Patients with tree pollen allergy and a history of the oral allergy syndrome will be recruited and their level of pollen sensitivity assessed by skin, blood and conjunctival tests. Sensitivity to apple will be confirmed initially in an open food challenge. After randomisation they will receive BP-SIT or matching placebo for 2 years. Apple sensitivity will be assessed by food challenge with disguised apple in a graded challenge design before treatment and again after 1 and 2 years, with parallel documentation of the impact of BP-SIT on skin, blood and challenge tests. Potential Impact Oral Allergy Syndrome is common and causes considerable distress to patients. Our patient survey shows this is important to patients, but data from Allergy UK and other patient groups suggest this is not taken as seriously by healthcare professionals as it should be. If the trial is successful, it would provide a new indication for specific immunotherapy that could be promoted nationally and give considerable benefit to large numbers of patients, allowing them to eat more fruit and vegetables, as well as improving their hay fever. A particular strength of this study is that it focuses on effectiveness on the fruit-related symptoms which patients say are really important to them.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the efficacy of "Boswellia frereana as a MMP 9 inhibitor in age-related inflammatory disease
Funder: The Dunhill Medical Trust

Abstract: Matrix metalloproteinases (MMPs) are a subclass of proteolytic enzymes that degrade extracellular matrix constituents during normal physiological events including tissue remodelling. However, the dysregulation of MMP activity, in particular MMP9, contributes to many pathological conditions including metastasis, arthritis and neurological disorders. Previously, we investigated the efficacy of Boswellia frereana (Somalian Frankincense) as an anti-inflammatory nutraceutical in an in vitro model of articular cartilage degeneration. In addition to potent anti-inflammatory properties, B. frereana selectively inhibited the synthesis and activation of MMP9, whilst expression levels of other MMPs and the aggrecanases (ADAMTS-4 and -5) were largely unaffected. This proposal seeks to determine whether B. frereana can be used as an MMP9 inhibitor. Identifying the “active” constituent(s), determining whether there is tissue specificity and whether B. frereana can negate the detrimental effects of different inflammatory mediators requires investigation. Clearly, the development of a selective MMP9 inhibitor offers great scope as a therapeutic to alleviate symptoms associated with age-related inflammatory pathologies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Perceptions of rheumatoid arthritis and decisions to seek help
Funder: The Dunhill Medical Trust

Abstract: Rheumatoid arthritis (RA) causes painful joint inflammation and is typically diagnosed between 50 and 60 years of age. RA is incurable, therefore, even those diagnosed with RA while young continue to manage their symptoms during their later years. If diagnosis and treatment of RA are delayed, irreversible joint destruction and disability occur. Unfortunately, there are often long delays before help is sought. At the onset of symptoms many people delay in seeking help for over 3 months. This project aims to explore public knowledge of RA and the way that people respond to the initial symptoms of RA. Multiple approaches will be undertaken including an explorative qualitative study, a vignette study, a cross-sectional survey and a review of informational resources. This research will enhanced our understanding of older peoples’ help seeking decisions and will inform the development of a public health intervention to promote early help seeking behaviour


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Selection of antibodies in older people
Funder: The Dunhill Medical Trust

Abstract: Immune systems of older people are less able to respond to pathogen challenge and are more likely to carry autoreactive antibodies. A restricted B cell repertoire correlates with ill health in the older person, and there are age-related differences in post-challenge responses to pneumococcal and flu vaccines. Our preliminary data indicate that the character of memory B cell populations changes with age and, surprisingly, that unchallenged B cell populations also change with age. The former indicates a change in the way the older immune system responds to exogenous antigen challenge, the latter implies an age-related change in the early developmental processes that occur in the bone marrow. We have bone marrow lymphocytes from 52 patients aged 27 to 86 and will determine whether these changes are intrinsic to the B cell development process (i.e. occur during Ig gene rearrangement) or whether they are a result of altered negative selection processes


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: 2005 RRG 8.47 - Predicting poor hand functional outcome in Rheumatoid Arthritis – a comparison of high-resolution ultrasound examination and occupational therapy clinical hand assessment
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Accurate assessment of joint activity and damage is essential in clinical management of rheumatoid arthritis (RA). Especially important are measures which predict poor prognosis for disability. This proposal examines the hypothesis that High-resolution ultrasound (HRUS) examination is more effective than clinical assessment in identifying patients most at risk of accelerated hand and wrist joint damage and disability. We plan to measure sonographic characteristics of hand and wrist arthritis alongside features derived from structured occupational therapy (OT) assessment at baseline and intervals over a three year period in patients with early RA compared with function and joint damage indicators (outcome assessments). Possible intervening variables will be measured during the study period. Analysis of study results will allow us to 1) propose simple and efficient tests to accurately identify which early rheumatoid patients are at highest risk of developing hand and wrist disability. 2) determine how useful is HRUS as a practical clinical tool for assessment, monitoring and prediction of hand and wrist outcome in early RA when applied in the clinic by appropriately trained rheumatologists compared with detailed clinical OT hand assessments. 3) define which OT hand and wrist assessments are most useful in predicting functional loss 4) outline the role played by individual components of inflammation measured by HRUS (synovial thickening, effusion, power Doppler signal intensity) in later development of damage and disability.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Secretion at the immunological synapse.
Funder: Wellcome Trust

Abstract: The goal of this research is to identify and understand the mechanisms that regulate secretion from cytotoxic T lymphocytes (CTL). The secretory granules of CTL are unusual as they are also the lysosomes of these cells, and the mechanisms controlling their secretion differ from those of secretory granules in other cell types. The primary aim of this proposal is to use human genetic diseases in which CTL function is impaired to identify novel proteins required for secretion from CTL. We will complement this approach with use of lentiviral expression in CTL to identify additional proteins involved in secretion which might give rise to embryonic lethal mutations. We will combine molecular, biochemical, microscopical and immunological techniques to dissect the molecular interactions required for each step leading to secretion at the immunological synapse. Using these techniques we will determine the role of cytoskeletal proteins, exocyst and SNARE proteins in CTL secretion. We will also examine the later steps of CTL killing, characterising the microenvironment of the secretory cleft and the mechanisms that lead to membrane acquisition from target cells by CTL, asking whether this mechanism plays a role in regulating the CD8 response and in preventing hemophagocytosis


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Coreceptor control of T cell cross-reactivity.
Funder: Wellcome Trust

Abstract: T-cells are key cells in the immune system and are some of the most important cells in our bodies because they: (1) Orchestrate immunity and are key elements in the control of infection; (2) They are important for the natural eradication of cancer; (3) They hold the key to successful vaccination; (4) They are an important factor in transplant rejection; (5) When they go wrong they are the cells that cause autoimmune diseases such as diabetes, arthritis and multiple sclerosis. T cells spring into action when the receptors on their surface recognize bits of microbes and cancer molecules called antigens. In order to deal with all possible infections, our T cells have to be able to recognize more than 1,000,000,000,000,000 different foreign' antigens. To achieve this, each individual T cell surface molecule can recognize more than 1,000,000 different possible antigens. Therefore T cells are extremely cross-reactive'. However if T cellsare too crossreactive they may start to attack our own body thereby causing disease themselves. So it is important that the level of T cell cross-reactivity is carefully controlled toprovide an immune response that is good but does not attack our bodies. I aim to understand how T cell crossreactivity is controlled.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Risk factors associated with non-atopic wheeze among migrant children in urban area of Ecuador. A case-control study.
Funder: Wellcome Trust

Abstract: The prevalence of allergic disease has increased dramatically over the past few decades in industrialized countries and is increasing at an alarming rate in urban centres in the non-industrialized world, but prevalence remains low in rural areas. There is strong evidence for an inverse relationship between allergy risk and geohelminth prevalence, and this has led to the suggestion that endemic geohelminth infection in rural areas may protect against allergic disease. Programmes for the control of geohelminth infections are now a widely implemented strategy targeted at school-age children. The candidate proposes to investigate the impact of long-term treatment with the broad-spectrum anthelmintic drug, ivermectin, on the risk of atopy and allergic disease in school age children living in rural communities in Esmeraldas Province in Ecuador. Semi-annual/annual treatments with ivermectin have been used for the past 10 years to control onchocerciasis in endemic communities in Esmeraldas Province in Ecuador, and the candidate will compare the prevalence of atopy and allergy in 40 rural communities that have received ivermectin with 40 comparable communities that have not received the intervention. The data will provide also the opportunity to examine individual versus community-level risk factors for allergic disease in the rural Tropics.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Specific Unresponsiveness to Alloantigens in vivo.
Funder: Wellcome Trust

Abstract: Transplantation is a successful way to treat people whose own organs stop working but to prevent rejection transplant recipients have to take potent immunosuppressive drugs for the rest of their lives. These drugs work, but as well as suppressing the response against the transplant, they suppress the entire immune system. As a result, transplant recipients have more virus infections than other people and an increased risk of developing cancer. Control is a key feature of normal immune res ponses. A response that is too half-hearted will not resolve an infection, while one that is over excessive will lead to tissue damage. Understanding how the immune system is controlled when it responds to a transplant, and promoting the development and function of cells that can prevent rejection selectively hold the key to reducing the unwanted side-effects of immunosuppression. This programme of work will focus on how, when and where specialised cells that can control transplant rejection work and what stops them from working. The results we obtain will also help develop new treatments for people who have autoimmune diseases, are allergic or have cancer, where controlling the immune system selectively is also critically important.


Research activity codes: 5.4 SURGERY
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Control of antigen processing by Fc receptors.
Funder: Wellcome Trust

Abstract: The body's immune system needs to decide how to react to the different stimuli it receives. It has to distinguish between the body s own cells and proteins (which need to be ignored or, if damaged, disposed of safely) and those derived from bacteria and viruses (which need to be rapidly degraded and processed to stimulate an effective immune response). Specialised immune cells called dendritic cells (DC) and macrophages are critical in deciding how to appropriately respond in these different si tuations. Failure of this process can either lead to the immune attack of the body s own cells (a condition called autoimmunity ) or a failure to control bacterial and viral invasion (leading to uncontrolled infection). The aim of my project is to understand how the response of DC and macrophages is controlled by a family of cell surface molecules called Fc gamma receptors (FcgammaRs) which recognise antibody-coated proteins, bacteria and cells. Dysfunction of FcgammaRs has been implicated in the development of autoimmunity and in susceptibility to severe bacterial infection. I will examine how naturally-occurring genetic variations in these receptors, found more frequently in patients with SLE or severe infections, affect how macrophages and DC respond to antibody-coated particles and bacteria.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A new player in MHC class I processing and presentation.
Funder: Wellcome Trust

Abstract: The immune system protects us from infection from pathogens, such as viruses, and also destroys cancer cells. A group of molecules called MHC (Major Histocompatibility Complex) molecules protect us from infection and cancer. MHC molecules are displayed on most cells in the body, where they let the immune system know what is going on inside cells and if there are any problems such as infection or if the cell is becoming cancerous. The MHC molecules are displayed as a specific shape. However, we have recently discovered a new molecule that changes the shape of MHC displayed on the cell. I would like to understand the role of this new molecule and these unusual shapes of MHC in our bodies and whether they are involved in helping us to fight infections and to destroy cancer cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigation of the lupus susceptibility gene, TNFSF4 (OX40L).
Funder: Wellcome Trust

Abstract: We have clearly established that the gene (TNFSF4) encoding OX40L is a significant susceptibility gene in systemic lupus erythematosus (SLE). OX40L is expressed on activated B cells and dendritic cells and provides accessory stimulation to T cells via its unique receptor, OX40. The genetic polymorphisms that predispose to SLE encompass the promoter and 5' region of the gene and we have shown that they increase the expression of OX40L. In this proposal we seek to investigate the molecular mechanisms by which changes in OX40L expression are influenced by genetic polymorphisms. We will explore how increased expression of OX40L may alter the function of the immune system and hence determine how altered OX40L expression predisposes to SLE. To achieve this goal we propose to study human cell lines, peripheral blood samples and renal biopsy tissue. However there are limitations to human studies hence we will generate a conditional murine Ox40l gene targeted knockout that will allo w a more detailed examination of the role of OX40L in murine lupus. We propose to establish whether inhibition of this molecule has a therapeutic potential in human disease by using this knockout and by blocking the OX40L-OX40 interaction in murine models of lupus.


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