A role for hepatic sinusoidal endothelial cell antigen presentation in the generation of immune tolerance in hepatitis C

Lead Research Organisation: University of Birmingham
Department Name: Sch of Geography, Earth & Env Sciences

Abstract

170 million people worldwide are infected with the hepatitis C virus (HCV). A significant proportion of infected individuals develop liver scarring (cirrhosis) and liver cell cancer. To access the liver cells which the virus can infect it enters the liver via blood vessels in the liver called sinusoids. These are lined by specialised cells - hepatic sinusoidal endothelial cells (HSEC) - which express receptors that can bind HCV.

In health these cells play an important role in scavenging food proteins and other molecules from the blood and can interact with cells of the immune system. The effect of this interaction is to prevent the immune system from destroying harmless food proteins by a process called immune tolerance. We hypothesise that HSEC are critical in HCV infection by 1) taking up the virus from blood and concentrating it in the liver and 2) inducing immune tolerance to the virus, preventing its effective clearance from infected liver cells.

We will study HSEC from human tissue to determine how they interact with HCV and the immune system in HCV infection. Increased understanding of this critical aspect of the disease will allow us to develop new therapies to prevent chronic infection with HCV.

Technical Summary

Hepatitis C virus (HCV) infects an estimated 170 million people worldwide. A significant proportion of infected subjects are at risk of developing serious progressive liver disease. HCV is likely to enter the liver through the sinusoidal blood and come into contact with hepatic sinusoidal endothelial cells (HSEC) before infecting hepatocytes. The host groups have shown that HSEC express receptors known to interact with the virus but do not permit viral entry.

The immune response to HCV infection is often blunted and this results in a failure to clear the virus and chronic liver injury. The role of HSEC in the immune response to HCV infection is poorly understood. HSEC do scavenge macromolecules and can process and present antigen. Antigen presented in this way to naïve CD4+ T lymphocytes promotes tolerance rather than immunity. HSEC also express Toll-like receptors (TLR) and are therefore involved in both the innate and adaptive immune response.

We hypothesise that HSEC play a major role in viral persistence by concentrating virus in the sinusoids and by promoting HCV antigen specific tolerance. We will examine this by first defining the immunophenotype of HSEC in vitro and in vivo. Specifically, we will examine HSEC expression of the C-type lectins, scavenger receptors and TLR by immunohistochemistry, qRT-PCR, cell based ELISA, confocal microscopy and flow cytometry. We will also examine the effect of receptor activation on the profile of induced cytokines by multiplex bead array. Subsequently we will determine the effect of HCV and virus encoded proteins on HSEC function, receptor expression and cytokine secretion in vitro. We have previously shown that co-culture of HSEC with hepatocytes reduces HCV infection and we will determine whether HCV antigen exposure modulates HSEC proliferation, adhesion molecule expression and cytokine secretion. Finally we will compare antigen presentation by HSEC and dendritic cells (DCs) isolated from HLA-A2 donors, where wel-defined HCV epitopes exist. Lymphocyte proliferation will be determined by CFSE labelling and the nature of activation by the measurement of secreted and intracellular and secreted cytokines.

We believe that HSEC by promoting HCV antigen specific tolerance play a key role in the development of chronic HCV infection. Improved understanding of factors that promote chronic HCV infection allows the development of rational novel treatments for this important disease.

Publications


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Armstrong MJ (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. in The New England journal of medicine
Rowe IA (2016) Effect of scavenger receptor class B type I antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation. in Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
Rowe IA (2012) Assessment of the quality of evidence underlying international guidelines in liver disease. in The American journal of gastroenterology
 
Guideline Title EASL clinical practice guidelines: management of hepatitis C virus infection
Description Removal of recommendation for hepatitis A vaccination from guidelines for management of patients with hepatitis C virus infection
Geographic Reach Asia 
Policy Influence Type Citation in clinical guidelines
 
Description Roche Organ Transplant Research Foundation
Amount £204,384 (GBP)
Organisation Roche Organ Transplantation Research Foundation (ROTRF) 
Sector Charity/Non Profit
Country Switzerland, Swiss Confederation
Start 10/2011 
End 10/2014
 
Description MRC Centre for Immune Regulation 
Organisation Medical Research Council (MRC)
Department MRC Centre for Immune Regulation
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution Clinical research study
Collaborator Contribution Core facilities
Impact Pending
Start Year 2009
 
Title ITX5061 in liver transplant recipients 
Description This drug was the first host targeting entry inhibitor trialled in hepatitis C infection. The study done in Birmingham was the proof of concept study for applicability in liver transplantation. The study identified an effect of treatment but this was not sufficient for further clinical development. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status Closed
Clinical Trial? Yes
Impact As an experimental medicine study detailed information regarding the kinetics of hepatitis C virus (HCV) in the plasma were collected together with tissue samples from the explanted liver. These samples have enabled a greater understanding of the genetic evolution of HCV, informing studies of viral resistance to conventional antiviral treatments. 
 
Description World Hepatitis Day Event - Birmingham 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Presentation to patient groups, media and Chair of Cross-party Committee on Liver Disease

Positive feedback regarding importance of basic research in disease mechanisms
Year(s) Of Engagement Activity 2009