NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of lymphoid tissue inducer cells and tumour necrosis family members in the survival and function of regulatory T cells
Funder: Wellcome Trust

Abstract: Regulatory T cells (Tregs) are critical for preventing damaging T cell driven,particularly CD4 driven, immune responses against self. Accumulating evidencesuggests, that like memory T cells, they can be selected in thymus (tTregs) orinduced in the periphery (iTregs) by specific self or harmless foreign antigens. Our recent studies have shown that lymphoid tissue inducer cells (LTi), through expression of the TNF-ligands for OX40 and CD30, are critical for the survival of conventional memory CD4 T cells. The aim of this researchproposal is to dissect whether LTi also regulate the survival of antigen-selected Tregs at sites distant from the location they were selected. Second, we wish to further understand the role of OX40 and CD30 in regulatingtheir survival but also whether other TNF receptors, CD27 in particular, are involved in their regulatory function and survival.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Mechanisms that regulate T cell responses and their failure in autoimmunity.
Funder: Wellcome Trust

Abstract: The major cause of autoimmunity is when a type of white blood cell, called a T cell, makes an immune response against one or more organs or tissues in the body. T cells are very important for mounting immune responses that protect us against foreign pathogens, such as bacteria and viruses, and there are a number of failsafe mechanisms that generally prevent them making a response against self-tissues. Some people carry mutations in genes that put them at higher risk of developing autoimmunity. A number of these genes influence how T cells behave and these mutations increase the possibility that T cells mount a response to self-tissues. Our research is focused on trying to understand how and why these genetic mutations alter the behavior of T cells. We are trying to identify biochemical pathways inside the T cells that become disregulated by these mutations. The primary aim of our research is to pinpoint pathways that go wrong so that we can use this information to develop biomarkers th at will indicate risk of developing disease and aid in optimizing treatment and additionally to develop therapies that target these disregulated pathways.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Identification of novel gd T-cell ligands cells using a forward genetic screenin haploid human cells.
Funder: Wellcome Trust

Abstract: ãä T cells are a unique subset of T cells which do not require antigen processing and subsequent presentation by major histocompatibility complex (MHC) molecules, but instead recognise antigens directly. However, very little is known about the mechanisms of ãä T-cell ligand recognition. Therefore, we propose a novel gene-trap mutagenesis approach in human haploid cells to identify novel ãä T-cell ligands. There are four primary objectives that need to be met to carry out a successful screen using human ãä T cells and the near-haploid KBM7 cells: (i) establish specific ãä T-cell lines of interest; (ii) prove susceptibility of KBM7 cells to lysis by the particular ãä T-cell subset; (iii) mutagenise the KBM7 cells and


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Wellcome Trust Clinical PhD Programme at the University of Oxford: 'Lymphocyte depletion and regulatory T cell therapy'.
Funder: Wellcome Trust

Abstract: Transplantation is the treatment of choice for end-stage organ failure but long-term outcomes remain disappointing due to incompletely controlled rejection and the complications of immunosuppression. Operational tolerance, where short-term therapy promotes long-term survival without immunosuppression, can be achieved mouse transplantation models. This is often dependent on graft-protective CD4+CD25+Foxp3+ regulatory T cells (Treg). However, successful regulation of rejection is unlikely using Treg as a monotherapy because of the high precursor frequency of alloreactive T cells. We propose to determine whether reducing the frequency of these by lymphocyte depletion allows Treg therapy to control transplant rejection in immunocompetent mouse recipients. We have already demonstrated prolongation of skin allograft survival using Alemtuzumab and Treg in a transgenic mouse expressing human CD52. Further work will aim to establish operational tolerance in both skin and vascularised heart graft recipients. We also propose: 1. to assess the importance of alloantigen priming by comparing natural with induced Treg. 2. to examine the effects of this strategy on pre-existing memory responses. 3. to apply our findings in humanised mouse models. The findings of this investigation will not only address mechanistic questions in transplant immunology but also be of direct relevance to clinical trails commencing in this centre.


Research activity codes: 6.4 SURGERY;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Infection, Immunology and Translational Medicine - 'Investigating the mechanism of non-catalytic tyrosine phosphorylated receptor triggering'
Funder: Wellcome Trust

Abstract: The central goal of this project is to investigate the mechanism of non-catalytic tyrosine phosphorylated receptor (NTR) triggering. These receptors share a number of features. For example, they contain, or associate with adaptor molecules that contain, tyrosine residues that are phosphorylated by extrinsic kinases, and have comparatively small extracellular domains which bind surface-associated ligands. Our hypothesis is that the kinetic-segregation model, initially proposed to explain T cell receptor triggering, applies to all othermembers of the NTR family. A number of recent reports including work with natural killer cell receptors have provided evidence to support this notion. This project aims to develop and validate a number of generic techniques for systemically investigating the mechanism of NTR triggering and testing the KS model. Imaging, biochemical studies and functional assays will all be utilisedto aid in this. In parallel, a more in-depth analysis of a small subset of NTRs from various subgroups of the family, including leukocyte-associated immunoglobulin-like receptor 1 will be conducted. These experiments will complement the artificial system developed for large-scale systemic investigations of numerous NTRs, by utilising more physiological settings, including the use of natural ligands and primary cells that normally express the NTR.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The relevance of regulatory T cell conversion to T helper 17 for the balance between tolerance and inflammation.
Funder: Wellcome Trust

Abstract: The immune system protects against infections, e.g. invading viruses. This essential job is accompanied by pain and redness, known as inflammation , because some collateral damage to surrounding areas is caused by pro-inflammatory cells when attacking infections. In conditions called autoimmune diseases, pro-inflammatory cells are over-active even without infection as the trigger because they are not properly kept in-check by the immune system, resulting in significant damage to normal ti ssues. One of the key controllers of pro-inflammatory cells is a cell type called a regulatory T cell (Treg), without which humans rapidly develop fatal autoimmune diseases. We are growing Tregs outside the body in order to give them to patients with autoimmune diseases as a treatment. But, we have found that when Tregs are exposed to simulated inflammation in a test-tube they actually convert to the pro-inflammatory, or harmful, type. This conversion has significant implications for our under standing of development of autoimmune diseases and raises concern over potential complications of giving Tregs to patients who already have inflammation. Here, we propose to investigate Treg conversion by identifying which type of Tregs convert in the body; the biological importance of conversion; its mechanisms; and whether we can prevent/reverse it with different drugs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the links between inflammation and fibrosis during tissue repair.
Funder: Wellcome Trust

Abstract: RESEARCH QUESTION ABSTRACT ONLY Using three complementary model systems (zebrafish, tissue culture and mice) I want to ask three overarching questions related to how inflammation impacts on fibrosis/scaring: 1. How are inflammatory cells drawn to, and resolve away from, wounds and how do they interact with cells at the wound site? 2. How do wound fibroblasts change their collagen deposition behaviour in ways that lead to fibrosis, and how is this influenced by signals from inflammatory cells? 3. How can we modulate vari ous steps in the link between inflammation and wound fibrosis in order to reduce scarring?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Cross presentation of antigens by human CD141+ lung dendritic cells.
Funder: Wellcome Trust

Abstract: In haematopoetic stem cell transplant (HSCT) or 'bone marrow transplant', individuals are given a new immune system to help eliminate otherwise incurable diseases. A major barrier to health and survival after HSCT is graft versus host disease (GVHD). GVHD is a type of autoimmune condition. It arises because the new immune system sees the patients' tissues as threatening and attempts to destroy them. Severe inflammation of the skin, gut, liver and lung can result. Dendritic cells are known t o have an important role in triggering GVHD. Dendritic cells digest molecules posing a threat to the body. They display these molecules to other immune cells and stimulate immune reactions. These reactions can be helpful, for example in clearing infection, but they can also be harmful, for example in GVHD. We do not know the exact role of dendritic cells in lung inflammation following HSCT. Lung inflammation is commonly fatal and difficult to diagnose. From existing research, we think a type of dendritic cell (CD141+DC) may be critical. Our research aims to discover the location and functions of this cell in lung and whether it might trigger GVHD. Understanding the immune processes of this condition will help generate better tests and treatments.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Principles of early T-cell activation.
Funder: Wellcome Trust

Abstract: White blood cells, or leukocytes, form part of the immune system and help to control infections and prevent cancer in healthy people. People with autoimmune diseases such as lupus or diabetes become ill because their immune systems, including the leukocytes, turn against them. Leukocyte behaviour is largely controlled by proteins or receptors expressed on their surfaces, but how these receptors work is one of the great mysteries of the immune system. Mechanisms that appear to explain how other r eceptors function dont seem to apply to receptors on leukocytes, suggesting that new biology is involved. This gap at the centre of our understanding of the immune system is probably constraining our attempts to treat autoimmunity safely. We will use very new developments in microscopy that now allow us to study receptors at the single-receptor level on living cells, to distinguish between the major theories of receptor function. We will then examine how the T-cell integrates or transforms the i nformation conveyed by these receptors into specific cellular responses, such as cell activation. Finally we will apply our observations to the development of new treatments for autoimmunity, based on artificially enhancing the functions of receptors that block activation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Predicting efficient T cell activation with therapeutic applications.
Funder: Wellcome Trust

Abstract: T cells are white blood cells that continuously patrol the body in search of evidence of infection or cancer and they recognize these agents when receptors on their surface directly bind to fragments or 'antigens' derived from infectious organisms or cancer cells. The process of antigen recognition has been extensively studied in the hope that this knowledge can be exploited for the development of therapies that re-direct T cells to kill infected or cancerous cells. Immunologists have characteri zed the proteins involved in antigen recognition but because they interact in complicated ways it is difficult to predict how manipulating specific proteins will alter antigen recognition. This is an example of a complex system, such as transportation networks, ecosystems or computers, whereby changing one component often alters the whole system in unpredictable ways. My proposed research aims to build mathematical models that capture the complex protein interaction network that immunologists ha ve established. These models, once validated using experiments with T cells, can then be used to predict how specific protein modifications alter antigen recognition. Often the results are non-intuitive, underlining the need for mathematical models. My ultimate goal is to use these models to understand existing therapeutics and to design new ones.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigation of factors necessary for dendritic cells to initiate autoimmunity.
Funder: Wellcome Trust

Abstract: Autoimmune diseases occur when the immune system, which is normally tolerate to the bodys own tissues, mounts an inappropriate response towards the hosts own organs. This process can result in debilitating and life threatening diseases such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis. It is now well established that healthy individuals have T cells, which are the immune cells that frequently cause autoimmune pathology, that are able to respond to the bodys own tissue. These c ells do not normally cause disease beause the body has a range of protective measures that prevent dendritic cells (DCs), which are the specialised immune cells that control the function of T cells, from activating these potentially harmful cells. However, in some circumstances DCs are able to produce factors that enable T cells to overcome these protective mechanisms resulting in the development of autoimmune diseases. The aim of this project is to establish what DC factor(s) are necessary t o initiate, re-trigger and restrain T cells that have potential to damage the bodys own tissue. It is hoped that a better understanding of these key immunological processes will offer insights into how autoimmune diseases can be prevented and potentially cured.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Regulation of dendritic cell survival and function by synovial fibroblasts.
Funder: Wellcome Trust

Abstract: Rheumatoid arthritis (RA) is a condition in which an individual's immune system reacts against their joints leading to inflammation and can eventually cause severe disability. Dendritic cells are the generals of the immune system. They sense danger around them and marshal immune cells to attack. The commands they give are influenced by their surroundings so they know whether to strike. In RA they tell immune cells to attack the joint. Synovial fibroblasts produce fluid to lubricate the joi nt. However in RA they show characteristics we usually see in cancerous cells. They have been shown to attract immune cells to the joint, trap them there and keep them alive and activated. Surprisingly we know very little about how RA synovial fibroblasts interact with dendritic cells but we suspect they incorrectly tell dendritic cells that there is danger so they direct other immune cells to act in a more damaging way. If so we might be able to interfere with this and reduce inflammation. O ur aim is to identify the danger messages that RA synovial fibroblasts send to dendritic cells, alarming them and changing their behaviour. By doing so we may be able to improve arthritis by intercepting these messages.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigation of signal integration by non-catalytic tyrosine phosphorylated receptors in leukocytes
Funder: Wellcome Trust

Abstract: This work will investigate signal integration in cells through analysis of non-catalytic tyrosine-phosphorylated receptors (NTRs). NTRs are a recently described group of leukocyte cell-surface receptors [1, 2] that share a numberof features, including: i) they contain, or associate with adaptor molecules that contain, tyrosine residues that are phosphorylated by extrinsic kinases such as Lck; ii) they have relatively small extracellular domains (<20nm); iii) they bind surface-associated ligands. I will focus on analysis of interactions between NTRs containing immunoreceptor tyrosine-based activating motifs (ITAMs) and those containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Key goals of the research include: 1) To develop a system for analysis of signal integration at the cell surface 2) To determine whether matched sizes of receptor/ligand pairs are required for signal integration of ITIM- and ITAM-containing receptors 3) To determine the importance of the length of the intracellular tail of ITIM-containing NTRs for inhibitory efficiency


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Epidemiological mapping of podoconiosis in Ethiopia .
Funder: Wellcome Trust

Abstract: Podoconiosis is a disfiguring swelling of the leg that imposes social and economic burdens on affected individuals. Through its effects on productivity, it significantly compromises the development of endemic communities. Podoconiosis was recently included on the World Health Organization list of Neglected Tropical Diseases, yet control of this disease at national or sub-national level is still in its infancy. The Ethiopian Federal Ministry of Health has recognized podoconiosis as a priority fo r control, and indicated that the first step towards a coordinated national program is nationwide mapping. The mapping proposed in this Training Fellowship has the support of the Ministry of Health, which will facilitate ethical clearance and assign staff and vehicles at Zonal level. Kebede Deribe, the Training Fellow, will bring his experience of working with government and non-government organizations and his strong public health background to this project. Supervised by experts spatial epidem iology and in clinical and epidemiological aspects of podoconiosis, he will develop an efficient technique to map the disease nationwide. This new technique will generate information essential to the planning of podoconiosis control within Ethiopia, and will be made available to other podoconiosis-endemic countries.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Wellcome Trust Joint Basic and Clinical PhD Programme at the University of Birmingham: Antigen receptor diversity and autoantibody characterisation in Common Variable Immunodeficiency
Funder: Wellcome Trust

Abstract: Common Variable Immunodeficiency (CVID) is a disorder characterised by poor antibody production resulting in recurrent infections, autoimmune diseases andmulti-organ complications. The current treatment of CVID is effective in controlling infections but it does not tackle the disease complications nor does it restore normal immune functions. The cause of CVID is still largely unknown but it is thought to be a conditionacquired later in life as most cases present in adulthood and do not run in the family. Over the past year, our laboratory has identified some significant abnormalities in the T-cell compartment of the immune system in a small numberof patients with CVID. These finding could be the first step to elucidate an underlying cause of CVID and designing better therapy. We aim to expand our work by studying a larger number of patients and continue to characterise these abnormal cells. This research project will be carried out in dr Cobbold's laboratory at the MRC centre for Immune Regulation which has an excellent track record of T cellresearch. Patients will be recruited from the West Midlands Primary Immunodeficiency centre which is one of the largest clinical Immunology unit in the UK.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: An Economic Evaluation of Paediatric Allergy Services in the West Midlands.
Funder: Wellcome Trust

Abstract: It is now well documented that allergies are increasing and that UK has amongst the highest numbers of allergy sufferers worldwide. However, there are very few allergy specialists in the country (none in Midlands) and GPs are often not trained adequately in dealing with these patients. The aim of our project is to understand the current levels of allergy in the Midlands, to document the services available for children and young adults with allergies locally and to estimate costs and outcomes associated with various different pathways for delivering allergy services. We will first contact hospitals in the region to ascertain the current allergy services in the West Midlands. We will look at various databases to estimate the current burden of allergy. We will then ask patients as well as GPs to state their preferences for allergy services in the region using a method known as discrete choice experiment. We will also be interviewing some GPs and patients (and parents). Using pub lished data and those from a community allergy project in London, we will then estimate the costs and possible benefits of changing the current allergy services. This project will help us understand (and hopefully improve) allergy services in the region.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The study of immune cell development by stem cell mutagenesis.
Funder: Wellcome Trust

Abstract: Embryonic stem cells have the potential to form hundreds of different cell types in our body. This includes dozens of different white blood cells whose primary purpose is to provide immunity against infection. Interrupting the developmental pathway between stem cell and immune cell will weaken our immune system, while overactivating it can lead to autoimmune disease or leukemia. Using both embryonic stem cells and specialised blood stem cells, our goal is to uncover the molecules needed to creat e immune cells. This knowledge will improve our ability to create patient-specific immune cells for use in cell therapy, as well as providing new targets for the control of autoimmune disease and leukemia.


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