Immune cells in Inflammatory Bowel Disease
Research type
Research Study
Full title
Immune cells in inflammatory bowel disease
IRAS ID
171175
Contact name
Graham Lord
Contact email
Duration of Study in the UK
5 years, 0 months, 9 days
Research summary
Research Summary
Inflammatory bowel disease (including ulcerative colitis and Crohn's disease) are common medical conditions involving serious inflammation of the small and large bowel. These often cause troubling symptoms such as abdominal pain and bloody stools. Current medical treatments are not effective for everyone and can cause potentially serious side effects. Many people with IBD require bowel surgery. Consequently, better and more effective treatments are required.
This application proposes to look at the role of immune cells in IBD. Tregs reside in the blood and tissues, where they interact with other immune cells suchs as ILC (innate lymphoid cells) and DC (Dendritic Cells) and prevent inappropriate inflammation. Immune cells from people with IBD appear to be dysfunctional and do not adequately suppress gut inflammation. The first aim is to compare Tregs and other immune cells in people with IBD and "healthy controls", which would help to glean insights into the nature of this dysfunction and therefore the pathogenesis of IBD.
The Biomedical Research Centre (BRC) has an ongoing programme of growing Tregs in the laboratory. With the advent of licensed facilities on site (the GMP unit and Clinical Research Facility), the BRC will have the capacity to use these cells in clinical trials. We now know that we can expand clinical grade Tregs from patients with IBD. However, the optimal way to grow them and make them go to the appropriate inflamed site is as yet unknown. The second aim of this application is to determine the best way to grow Tregs and make them go to the gut. This will require Tregs and other immune cells to be isolated from blood, colonic and associated adipose tissue of patients with inflammatory bowel disease.
The studies proposed in this application will help develop important new therapy for IBD.Summary of Results
At present, doctors still have an incomplete understanding of what causes IBD. Evidence suggests that patients inherit a mix of genes, some of which put them at increased risk of developing IBD, and that in combination with environmental factors, such as diet, stress, and changes in gut bacteria, some people go on to develop the disease.
Over the course of this study period, we have performed experimental work on blood samples provided by patients with and without IBD. This work has allowed us to identify genetic changes which put patients at risk of developing IBD.
A focus of the work has been on a subset of immune cells which play an important role in the development of IBD, called regulatory T cells (Tregs). These cells act to control inflammation, and IBD patients tend to have a reduced number or function of Tregs. We have identified the mechanisms by which Tregs are less active in IBD, and the optimum conditions in which to grow them to restore their function. This work forms the basis of a clinical trial to give patients cell therapy with Tregs.
We have also studied the impact of one particular inherited genetic change on the behaviour of patients’ immune cells. This genetic change is given the code ‘rs61839660’, and is carried by about 1 in 10 patients with Crohn’s disease. Our ultimate wish was to identify whether by understanding the effect of this genetic change, we could find a new treatment for these patients, as well as learning some more general features of the process by which immune cells contribute to inflammation in IBD.
We found that in patients who carried the rs61839660 genetic change, there were differences in types of their immune cells called regulatory and effector T cells. Regulatory T cells generally suppress inflammation, but effector T cells contribute to inflammation – the balance between these cell types is therefore very important. In patients with the genetic change, the balance between regulatory and effector T cells was upset such that effector T cells were more active, and we believe that this could contribute to gut inflammation in these patients. The effector T cells from these patients also released more of an inflammatory chemical called ‘cytokines’ when stimulated. We were able to treat patients’ cells in the lab with a medication which blocks the over-active effector cells.
At present, this area of research remains lab-based, and we are continuing our research in order to understand exactly what this genetic change means for patients. We hope that, in time, we will be able to understand which treatments are most likely to benefit patients with this genetic change, and which could cause them harm. The aim will be to ensure that these patients get the best treatment specifically for them.
REC name
London - Riverside Research Ethics Committee
REC reference
15/LO/0151
Date of REC Opinion
12 Feb 2015
REC opinion
Favourable Opinion