Can T-cell receptor sequencing and gene expression profiling deliver personalised therapy in Immune Thrombocytopenia?
Lead Researcher : Dr Amna Malik
Immune thrombocytopenia (ITP) is a blood disorder due to low platelet count, a type of blood cell that prevents bleeding. In ITP, the immune system (including antibodies and T cells, a type of white blood cells that play an important role in fighting infections) attacks and destroys platelets, leading to bleeding problems such as easy bruising, nosebleeds, and heavy menstrual bleeding. There are many new treatments now available for patients with ITP, but not everyone responds to each treatment, and some people must go through many treatments before getting a response. This is very frustrating for patients. In addition, some patients do not respond to any treatment and have what is caused refractory ITP (a disease that does not respond to any treatment).
We are running a trial to study whether there are different types of ITP by looking at the immune cells in great detail from ITP patients – this is called immune profiling. We have recently found that some ITP patients who don’t respond to lots of treatments have expanded T cell clones (one part of the immune system) with some abnormal featureswhich we think could be causing the ITP not to respond to treatment.With further analysis we may identify different types of cells in individual patients with ITP. We will see whether the types of abnormal cells can help us to predict what kind of treatments people will respond to. This could help us to decide which treatment is best for an individual patient and might help us to design more targeted treatments.
Update: We have now completed sample collection and collected clinical information for all the study participants. We have conducted genetic analysis of the ITP trial patient’ immune cells and are now in the process of analysing the data.
Endothelial dysfunction in thrombotic autoimmune disorders
Lead Researcher : Dr Deepa Jayakody Arachchillage
In health, the lining of the healthy blood vessels (endothelium) protects against blood clot formation by making anti-coagulant (clotting) proteins and keeping the vessel in a relaxed and open state allowing blood to flow freely. Autoimmune diseases such as antiphospholipid syndrome and systemic lupus erythematosus are known to impair the function of the endothelium which results in increased blood vessel wall stickiness. This can then cause blood clots, failure to break down the clots, and damage to organs such as the kidneys and cause heart attacks and stroke.
We can find out how damaged the vessels are from measurements of proteins in the blood using blood tests, but these do not provide a complete assessment of how well the blood vessel is functioning. In this study, we propose to assess blood vessel function of patients with autoimmune disease (Antiphospholipid syndrome, systemic lupus erythematosus and rheumatoid arthritis) by using a new non-invasive device called an EndoPAT which is generally well tolerated (based on the feedback from patients participated into studies assessing other diseases affecting blood vessel function). This simple device comprises a blood pressure cuff and two probes which are fit like gloves, over the forefinger in each arm. This gives us a measure of how well the blood vessels can relax when needed. As well as comparing these results with those from the blood and clinical events (such as recurrent blood clots or bleeding), we can understand the impact of treatments on the blood vessels. If successful, we will use this EndoPAT in larger trials of new treatments for all autoimmune disease.
Update: We have recruited 83 patients and 16 healthy controls. We did preliminary analysis of the some of the data from the project and submitted an abstract to the International Society for Haemostasis and thrombosis meeting in Bangkok (end of June 2024) and will know the outcome of the submission by early
Spatial multi-omic analysis of temporal artery biopsies to identify novel therapeutic targets and biomarkers for care optimisation in giant cell arteritis
Lead Researcher : Dr Robert Maughan
Giant Cell Arteritis (GCA) is a disease where a person’s immune cells attack their own arteries, particularly those of the head. GCA can have severe effects on patients lives, the arterial damage caused by the disease can result in severe headaches, stroke or even blindness. To control the disease, treatment with lengthy courses of powerful immune suppressing drugs called glucocorticoids (“steroids”) is required. Unfortunately, glucocorticoids have significant side effects including the development of diabetes or heart disease. Another important problem is the lack of blood tests available to accurately monitor the disease and gauge progress in treating it. As a result, patients are frequently over- or under-treated.
To develop the new treatments and blood tests that are urgently required in GCA, we first need to identify the key cell-types and proteins driving the disease. In this project, we will use a powerful new technology called “spatial transcriptomics” to study artery biopsy samples obtained from patients at diagnosis. This method provides a detailed picture of what proteins are being produced at each location in diseased arterial samples. By combining this analysis with previous work where we identified a series of proteins that are increased in the blood of GCA patients, we will identify high priority targets for the development of new treatments and blood tests. Promising drug targets will be further explored in pre-clinical studies while the value of new blood tests will be confirmed in large studies of patients followed over time.
Update:We have completed the first phase of the project which involved the identification of proteins in blood which are increased in active GCA. We are midway through the second phase in which we will carry out spatial analysis of arterial samples from GCA patients and link these findings to what we have seen in the blood.
Optimizing B cell therapy response in lupus through comprehensive characterization of peripheral blood immune cells
Lead Researcher : Charlotte Bottomley
Systemic lupus erythematosus (SLE) is an autoimmune illness in which the immune system of the body unintentionally causes inflammation and damage to tissues. SLE particularly affects the joints and skin and is an important cause of kidney failure in young people. In SLE the immune system makes antibodies that bind to proteins in our tissues. We call these autoantibodies. Antibodies usually only bind to proteins that are not part of the body, for example proteins on the surface of a bacteria. Antibodies are important in protecting us against infection, but autoantibodies in SLE damage our tissues such as the kidney. One way to reduce autoantibodies and their damaging effects is to use drugs that target B cells (a type of white blood cell ) ) since B cells are important in autoantibody production in SLE. These drugs include rituximab, belimumab and most recently an innovative approach that uses cells to target the abnormal B cells in SLE. In the Imperial Lupus Centre, where we care for over 500 individuals with SLE, we have been studying how to identify who will respond to B cell therapy and which approach to use. We do this by collecting blood samples in clinic and measuring proteins in the circulation and the changes in a type of blood cell called a peripheral blood mononuclear cell (PBMCs). Specifically, we measure many proteins using state of the art technology ( e.g. NULISA, Alamer Biosciences; SomaLogic) and we measure changes in PBMCs by looking at changes in the genes that are switched on in these cells. In this project we are correlating changes in the proteins and PBMCs with disease activity over time and the response of the disease to rituximab and belimumab and other treatments. The aim is to be able to select the right treatment for the individual by assessing protein and gene changes in the blood before treatment starts. This is a collaborative effort and we have partnered with scientists at the Wellcome Sanger Institute in Cambridge.
Update: We have completed measurement of proteins in our cohort using both the SomaLogic method (measurement of 5000 proteins) and the NULISA method (very accurate measurement of 250 low abundance proteins). We have also completed accurate documentation of the disease features of the SLE cohort and the response to different treatments. We are now correlating the protein and clinical data. We have completed an analysis of PBMCs in patients treated with rituximab and that is under preparation for publication. We have also completed a large-scale analysis of PBMCs at the single cell level (work in collaboration with the Wellcome Sanger Institute in Cambridge and lead by Dr Emma Davenport).