Intrahepatic signals involved in the recruitment and differentiation of IL-17 secreting T cells and Regulatory T cells i
Lead Research Organisation:
University of Birmingham
Department Name: Immunity and Infection
Abstract
Liver disease is increasing in Western countries and there are nowhere near enough organ donors to treat the number of patients with end-stage liver disease. Chronic hepatitis leads to scarring (cirrhosis) and liver failure and the only effective treatment is liver transplantation. Lymphocytes are a type of white blood cell and an important part of the body‘s immune system. They normally fight infections but if they persist or become inappropriately activated they can cause liver injury as part of chronic hepatitis or inflammation that leads to scarring and liver failure. Lymphocytes are directed to sites of liver inflammation by molecules called chemokines that are produced in response to inflammation. These chemokines are specific in that they can direct the entry/ recruitment of particular groups of lymphocytes to specific tissues. These groups include damaging effector lymphocytes and regulatory cells which damp down inflammation leading to resolution of damage. The outcome of liver injury depends on the balance between these inflammatory and anti-inflammatory regulatory lymphocytes which in turn will be determined by a) which types of cells are recruited to the liver from blood b) signals within the liver that shape the survival, activation and expansion of specific lymphocytes. Shifting the balance towards anti-inflammatory regulatory cells may prevent liver inflammation and promote resolution thereby reversing progression to fibrosis/cirrhosis. We would like to investigate the molecular signals involved and then exploit our knowledge to develop novel therapeutic approaches using anti-inflammatory regulatory lymphocytes as cell therapy to treat chronic liver diseases.
Technical Summary
Hypothesis
Intrahepatic signals regulate the balance of effector regulatory networks in the human liver by shaping the recruitment and differentiation of functional t cells subsets.
The outcome of liver injury depends on the balance between inflammatory effector and anti-inflammatory response. In the proposed fellowship I will investigate this balance in human inflammatory liver disease by 1) defining signals that recruit and position Treg, Th1, Th22 and Th17 cells within the inflamed liver 2) defining the effect of the liver microenvironment and particularly dendritic cells and stromal cells on T cell survival and differentiation. I will also study the trafficking of autologous regulatory T cells after intravenous injection into patients with liver disease using MRI to determine homing and survival of Treg in vivo.
Aims and Design
1. Intra-hepatic signals regulate T cell subset recruitment to the human liver
I will use flow-based assays to determine endothelial and stromal cell factors that promote selective recruitment of effector versus regulatory T cells to the human liver. I will develop a human tissue assay to study post-endothelial migration of T cells in viable liver ex vivo in real-time. T cells and liver cells will be labelled with different fluorchromes and the migration of T cells through tissue tracked using Nipkov spinning-disc confocal microscopy.
2. Hepatic do stromal cells and dendritic cells regulate T cell survival and differentiation
I will study intrahepatic signals including those mediated through stromal cells that modulate T cell survival and differentiation using co-culture assays in which different cytokines and differentiation factors are added. The survival, plasticity and differentiation of Th1, Th17 and Th22 cells will be studied in Prof Paul Klenerman‘s laboratory in Oxford and the role of specific Th17 and Th122 differentiation factors will involve a collaboration with Dr Mark Veldhoen in Cambridge.
3. Homing of regulatory T cells in patients with autoimmune liver disease
The Birmingham NIHR Liver BRU has facilities and expertise to carry out cell therapy clinical trials. Within the BRU we are developing MRI to track infused cells in patients. I will use this technique to track infused autologous Treg isolated from the blood of patients with autoimmune liver disease. I have defined GMP-compliant methods for Treg isolation I will now optimise MRI labelling in collaboration with Prof Hannon (Centre for Physical Sciences of Imaging in the Biomedical Sciences) who has developed novel MRI labels for cell imaging. I will record migration and localization of infused Treg using our research-dedicated 3T MRI.
This project will provide an outstanding opportunity to continue my development as a translational researcher in immunology putting me at the forefront of cell-based therapy for liver disease.
Intrahepatic signals regulate the balance of effector regulatory networks in the human liver by shaping the recruitment and differentiation of functional t cells subsets.
The outcome of liver injury depends on the balance between inflammatory effector and anti-inflammatory response. In the proposed fellowship I will investigate this balance in human inflammatory liver disease by 1) defining signals that recruit and position Treg, Th1, Th22 and Th17 cells within the inflamed liver 2) defining the effect of the liver microenvironment and particularly dendritic cells and stromal cells on T cell survival and differentiation. I will also study the trafficking of autologous regulatory T cells after intravenous injection into patients with liver disease using MRI to determine homing and survival of Treg in vivo.
Aims and Design
1. Intra-hepatic signals regulate T cell subset recruitment to the human liver
I will use flow-based assays to determine endothelial and stromal cell factors that promote selective recruitment of effector versus regulatory T cells to the human liver. I will develop a human tissue assay to study post-endothelial migration of T cells in viable liver ex vivo in real-time. T cells and liver cells will be labelled with different fluorchromes and the migration of T cells through tissue tracked using Nipkov spinning-disc confocal microscopy.
2. Hepatic do stromal cells and dendritic cells regulate T cell survival and differentiation
I will study intrahepatic signals including those mediated through stromal cells that modulate T cell survival and differentiation using co-culture assays in which different cytokines and differentiation factors are added. The survival, plasticity and differentiation of Th1, Th17 and Th22 cells will be studied in Prof Paul Klenerman‘s laboratory in Oxford and the role of specific Th17 and Th122 differentiation factors will involve a collaboration with Dr Mark Veldhoen in Cambridge.
3. Homing of regulatory T cells in patients with autoimmune liver disease
The Birmingham NIHR Liver BRU has facilities and expertise to carry out cell therapy clinical trials. Within the BRU we are developing MRI to track infused cells in patients. I will use this technique to track infused autologous Treg isolated from the blood of patients with autoimmune liver disease. I have defined GMP-compliant methods for Treg isolation I will now optimise MRI labelling in collaboration with Prof Hannon (Centre for Physical Sciences of Imaging in the Biomedical Sciences) who has developed novel MRI labels for cell imaging. I will record migration and localization of infused Treg using our research-dedicated 3T MRI.
This project will provide an outstanding opportunity to continue my development as a translational researcher in immunology putting me at the forefront of cell-based therapy for liver disease.