Defining the cellular and molecular pathogenesis of ulcerative colitis
Lead Research Organisation:
King's College London
Department Name: Immunology Infection and Inflam Diseases
Abstract
Ulcerative colitis (UC) is an incurable disease of the guts which can affect men, women and children of all ages. It can cause severe abdominal pain, bloody diarrhoea, and even cancer and many patients require surgery to help with these symptoms and complications. What is particularly worrying is that this condition is becoming more common and nobody really knows what causes it or what the best treatment is.
This research aims to understand more about what causes UC and may lead to the development of new therapies.
Our recent work has given us great insight in to what is likely to be going on in UC. We have found that one particular gene in cells of the immune system can upset the balance between ?good? and ?bad? bacteria in the gut and trigger inflammation in the bowel.
The research showed that this gene (known as T-bet) controls the production of a key protein called TNF-alpha. Without T-bet, too much of this protein gets produced, which starts the process of inflammation in the gut. This in turn allows bacteria to cross from the gut into the body, which can aggravate the inflammation and cause ulcerative colitis. Our work is uncovering the ways in which the crucial balance between ?good? and ?bad? bacteria is maintained in the gut and what goes wrong when it is upset.
UC is one type of ?autoimmune disease? that occurs when the body?s immune system makes a mistake and attacks itself. This can be triggered by the breakdown of the barrier of cells that prevents immune cells from attacking bacteria in the bowel. We?ve found that the T-bet gene is essential for maintaining the integrity of that barrier ? it?s like a peacekeeper in our guts and without it, things can get nasty.
Knowing more about the events that lead to ulcerative colitis opens up several possible new ways to treat it. As well as developing drugs that affect T-bet, another approach might be to use special ?regulatory immune cells?, which have already proved effective at treating ulcerative colitis in mice.
These results are very important and we hope to study these mice in a more detailed way to discover new treatments for patients with this disease, such as giving back some regulatory T cells.
We aim to take these findings from the lab and turn them into new treatments to help patients as quickly as possible.
This research aims to understand more about what causes UC and may lead to the development of new therapies.
Our recent work has given us great insight in to what is likely to be going on in UC. We have found that one particular gene in cells of the immune system can upset the balance between ?good? and ?bad? bacteria in the gut and trigger inflammation in the bowel.
The research showed that this gene (known as T-bet) controls the production of a key protein called TNF-alpha. Without T-bet, too much of this protein gets produced, which starts the process of inflammation in the gut. This in turn allows bacteria to cross from the gut into the body, which can aggravate the inflammation and cause ulcerative colitis. Our work is uncovering the ways in which the crucial balance between ?good? and ?bad? bacteria is maintained in the gut and what goes wrong when it is upset.
UC is one type of ?autoimmune disease? that occurs when the body?s immune system makes a mistake and attacks itself. This can be triggered by the breakdown of the barrier of cells that prevents immune cells from attacking bacteria in the bowel. We?ve found that the T-bet gene is essential for maintaining the integrity of that barrier ? it?s like a peacekeeper in our guts and without it, things can get nasty.
Knowing more about the events that lead to ulcerative colitis opens up several possible new ways to treat it. As well as developing drugs that affect T-bet, another approach might be to use special ?regulatory immune cells?, which have already proved effective at treating ulcerative colitis in mice.
These results are very important and we hope to study these mice in a more detailed way to discover new treatments for patients with this disease, such as giving back some regulatory T cells.
We aim to take these findings from the lab and turn them into new treatments to help patients as quickly as possible.
Technical Summary
Ulcerative Colitis (UC) is an inflammatory bowel disease of unknown aetiology and rapidly rising incidence that causes significant morbidity and mortality and represents a significant unmet healthcare need.
We have recently developed a novel model of UC (TRUC=T-bet, RAG, Ulcerative Colitis) that begins to explain many aspects of this disease at a cellular and molecular level (Cell 2007; 131, 33-45). This model has been highlighted as revealing fundamental insight into disease pathogenesis (Cell 2007; 131, 15-17) and having particular relevance for translation (NEJM 2008; 358, 528-530). The absence of the transcription factor T-bet in the innate immune system causes a spontaneous, transmissible and fully penetrant colitis that is a phenocopy of human UC. The severity of this disease can be modulated by adoptive transfer of regulatory T cells (Tregs), antibody blockade of TNF-alpha and is also critically dependent on the gut microflora.
Based on a substantial body of new data, we will define our model in further detail and provide the translational platform for novel therapeutic modalities for human UC.
We will:
1. Determine the cellular and molecular mechanisms of disease pathogenesis.
i. As natural killer (NK) cells are hyperactivated in the TRUC mouse, these cells are probably important determinants of colitis. We will address this by antibody-mediated and genetic deletion of T-bet and NK cells in TRUC mice.
ii. At the molecular level, the defect appears to map to transcriptional repression at the TNF-alpha promoter by T-bet in colonic dendritic cells (DCs). We will test if DCs are critical for the pathogenesis of colitis by selective depletion of DCs utilizing the CD11c-DTR/GFP and T-betfl/fl x CD11c-Cre mouse.
iii. We have found that colonic epithelial apoptosis is the earliest histological event observed in the TRUC mouse. By crossing the TRUC model with the Lgr5 reporter mouse, we will be able to follow stem cell kinetics as colitis evolves to determine the role of the colonic epithelial stem cell in UC pathogenesis.
2. Elucidate the pathways that control colitis at a cellular, therapeutic biological and microbiological level.
i. We will investigate whether adoptively transferred Tregs directly control DC cytokine production.
ii. We will ascertain the most effective biological therapy for colitis.
iii. We will determine the cytokines involved in transmitted colitis and the response to biological therapy.
By validating these findings in parallel with human studies, we will translate our findings into real change in the management of human UC.
We have recently developed a novel model of UC (TRUC=T-bet, RAG, Ulcerative Colitis) that begins to explain many aspects of this disease at a cellular and molecular level (Cell 2007; 131, 33-45). This model has been highlighted as revealing fundamental insight into disease pathogenesis (Cell 2007; 131, 15-17) and having particular relevance for translation (NEJM 2008; 358, 528-530). The absence of the transcription factor T-bet in the innate immune system causes a spontaneous, transmissible and fully penetrant colitis that is a phenocopy of human UC. The severity of this disease can be modulated by adoptive transfer of regulatory T cells (Tregs), antibody blockade of TNF-alpha and is also critically dependent on the gut microflora.
Based on a substantial body of new data, we will define our model in further detail and provide the translational platform for novel therapeutic modalities for human UC.
We will:
1. Determine the cellular and molecular mechanisms of disease pathogenesis.
i. As natural killer (NK) cells are hyperactivated in the TRUC mouse, these cells are probably important determinants of colitis. We will address this by antibody-mediated and genetic deletion of T-bet and NK cells in TRUC mice.
ii. At the molecular level, the defect appears to map to transcriptional repression at the TNF-alpha promoter by T-bet in colonic dendritic cells (DCs). We will test if DCs are critical for the pathogenesis of colitis by selective depletion of DCs utilizing the CD11c-DTR/GFP and T-betfl/fl x CD11c-Cre mouse.
iii. We have found that colonic epithelial apoptosis is the earliest histological event observed in the TRUC mouse. By crossing the TRUC model with the Lgr5 reporter mouse, we will be able to follow stem cell kinetics as colitis evolves to determine the role of the colonic epithelial stem cell in UC pathogenesis.
2. Elucidate the pathways that control colitis at a cellular, therapeutic biological and microbiological level.
i. We will investigate whether adoptively transferred Tregs directly control DC cytokine production.
ii. We will ascertain the most effective biological therapy for colitis.
iii. We will determine the cytokines involved in transmitted colitis and the response to biological therapy.
By validating these findings in parallel with human studies, we will translate our findings into real change in the management of human UC.