Mucosal lymphocytes in the pathogenesis of Primary Sclerosing Cholangitis
Lead Research Organisation:
University of Birmingham
Department Name: Immunity and Infection
Abstract
Lymphocytes are a type of white blood cell and an important part of the body‘s immune system which fights infections. Lymphocytes are directed to sites of infection by molecules called chemokines that are produced in response to inflammation. These chemokines are specific in that they can direct the recruitment of particular groups of lymphocytes to specific tissues. If these chemokines are produced inappropriately lymphocytes can be recruited into tissue where they attack healthy tissue rather than the infection. We have shown that in Primary Sclerosing Cholangitis (PSC), a chronic form of liver disease that is closely associated with uncontrolled inflammation in the gut that there is aberrant production of gut specific chemokines in the liver which subsequently allows lymphocytes from the gut to be recruited to the liver and inappropriately cause liver damage. In this study we propose to examine exactly how these molecules are involved in PSC and whether we could exploit them as novel pharmaceutical targets to develop new drugs in the future to treat chronic liver disease.
Technical Summary
Hypothesis.
Primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease strongly associated with inflammatory bowel disease (IBD), is driven by the inappropriate recruitment of mucosal lymphocytes into the liver.
I have shown that mucosal T cells are recruited to the liver in PSC and will now address their precise role in disease pathogenesis by determining 1) the factors that initiate this process and 2) the role of mucosal T cells in initiating extrahepatic disease. These studies will define a new paradigm in which extraintestinal autoimmune disease can be initiated by T cells activated in the gut.
Aims and Design
1. What signals regulate mucosal T-cell homing to the liver?
We will use in vitro methods to determine how T cells are imprinted with gut tropism and whether under specific circumstances this can occur in the liver. The factors responsible for aberrant expression of gut addressins in the liver will be determined by a) treating human cells in vitro with combinations of cytokines, TLR agonists and microenvironmental factors b) experiments in genetically manipulated mice which I have shown express MADCAM-1 in the liver.
2. Murine models of PSC and in-vivo imaging
We will breed transgenic mice that express MAdCAM-1 and CCL25 in the liver and assess homing of gut T cells to the liver in adoptive transfer studies and in the setting of experimental IBD. These experiments will be initiated in the von Andrian lab in Harvard which is at the forefront of such work and where I will learn how to use multi-photon intra-vital microscopy to study homing to tissues in vivo.
3. Human in-vivo detection of mucosal lymphocytes.
I will generate T cells with a gut-homing phenotype and test their ability to home to the liver in patients with PSC using an indium111-based tracking protocol established in our group. Homing to the gut, liver, lungs and spleen will be assessed using scintigraphy to determine whether such cells show selective recruitment to the liver. We will use CCR9 and ?4?7 inhibitors that are currently undergoing phase 3 trials in IBD to determine the therapeutic potential of inhibiting these pathways. The facilities to carry out such studies to GMP standards are available through the National Blood Authority cell immunotherapy lab and the Wellcome Trust CRF.
Primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease strongly associated with inflammatory bowel disease (IBD), is driven by the inappropriate recruitment of mucosal lymphocytes into the liver.
I have shown that mucosal T cells are recruited to the liver in PSC and will now address their precise role in disease pathogenesis by determining 1) the factors that initiate this process and 2) the role of mucosal T cells in initiating extrahepatic disease. These studies will define a new paradigm in which extraintestinal autoimmune disease can be initiated by T cells activated in the gut.
Aims and Design
1. What signals regulate mucosal T-cell homing to the liver?
We will use in vitro methods to determine how T cells are imprinted with gut tropism and whether under specific circumstances this can occur in the liver. The factors responsible for aberrant expression of gut addressins in the liver will be determined by a) treating human cells in vitro with combinations of cytokines, TLR agonists and microenvironmental factors b) experiments in genetically manipulated mice which I have shown express MADCAM-1 in the liver.
2. Murine models of PSC and in-vivo imaging
We will breed transgenic mice that express MAdCAM-1 and CCL25 in the liver and assess homing of gut T cells to the liver in adoptive transfer studies and in the setting of experimental IBD. These experiments will be initiated in the von Andrian lab in Harvard which is at the forefront of such work and where I will learn how to use multi-photon intra-vital microscopy to study homing to tissues in vivo.
3. Human in-vivo detection of mucosal lymphocytes.
I will generate T cells with a gut-homing phenotype and test their ability to home to the liver in patients with PSC using an indium111-based tracking protocol established in our group. Homing to the gut, liver, lungs and spleen will be assessed using scintigraphy to determine whether such cells show selective recruitment to the liver. We will use CCR9 and ?4?7 inhibitors that are currently undergoing phase 3 trials in IBD to determine the therapeutic potential of inhibiting these pathways. The facilities to carry out such studies to GMP standards are available through the National Blood Authority cell immunotherapy lab and the Wellcome Trust CRF.