home » education & research centre » liver research group

  Liver Research Programme


The National Liver Transplant Unit at SVUH performs 50-60 transplants/year for end-stage liver disease caused by malignancy, infection, autoimmunity and toxicity. Since its inception in 1993, the transplant programme has been complemented by a research endeavour that seeks to understand the causes of these conditions and how they damage the liver. The overall aims are to harness the combined research and academic skills of medical, surgical and scientific liver specialists to:

a. improve patient care
b. modify current treatments so that more patients respond better
c. discover new therapies.


The SVUH research team, headed by Professors John Hegarty and Cliona O’Farrelly, was amongst the first in the world to describe a liver specific immune system and to explore some of the abnormalities in this system that underlie hepatic cancer and hepatitis C.

Refs:

 Phenotypic and Functional Changes of Cytotoxic CD56pos NT Cells Determine Outcome of Acute HCV Infection. Golden-Mason L, Castelblanco N, O’Farrelly C, Rosen HR.
J. Virol. 2007. 81(17):9292-8. PMID 17553896.

Liver Immunity and Tumour Surveillance Canning C, O’Brien M, Hegarty J, O’Farrelly C.  Immunology Letters 2006, 107 (2) 83-88.  PMID 17101177

Changes in hepatic immunoregulatory cytokines in patients with metastatic colorectal carcinoma: implications for hepatic anti-tumour immunity. AM Kelly, L. Golden-Mason, O. Traynor, J. Geoghegan, G. McEntee, J. Hegarty, C. O’Farrelly. Cytokine. 2006. 35 (3-4):171-179 PMID 16971136.

Reconstitution of Hepatitis C virus-specific T-cell-mediated immunity after liver transplantation. S.J. Weston, R. Leistikow, K. Rajender Reddy, M. Torres, A.M. Wertheimer, D.M. Lewinsohn, S. Chou, M. P. Davey, C. Corless, C. O’Farrelly, D.R. Nelson, H.R. Rosen. Hepatology. 2005. 41(1) 72-81. PMID 15619226


The success of the research groups has depended on excellent co-operation and communication between all the specialists required to run a successful liver transplant programme: surgeons, transplant co-ordinators, nurses, clinicians, pathologists and scientists. Together, we collect and collate valuable patient material and information in Biobanks (DNA blood and liver samples from Transplant, Liver Cancer and HCV patients) and Clinical Databases (clinical patient information). This data creates an essential resource and pool of information that provides material and clinical information essential for our research. All of this happened with ethical approval (provided after extensive review by the SVUH Ethics committee link)  and informed patient consent.


 

Collaborators:  

   Jim Johnston
   Derek Doherty
   Aideen Long
   Hugo Rosen
   Cormac Taylor
   Martin Leonard
   Mark Exley
   Christine Biron


The critical mass of research which was funded by over 3 million euros has generated over 30 international publications and provided research education for 12 students (MD, PhD, MSc). Contributions made to text books in Liver Immunology and Viral Hepatitis:

Lymphoid Repertoires in Healthy Liver. D.G. Doherty, C. O’ Farrrelly.
In ‘Liver Immunology’ 2002 (Eds Michael Manns, Eric Gershwin) pp 31-46. Hanley & Belfus, Inc. Philadelphia

The Role of the Liver in the Immune System C. O’Farrelly, R.H. Pierce, I.N. Crispe
In ‘Viral Hepatitis, 3rd Edition’ 2004 (Eds Howard Thomas, Arie Zuckermann, Stan Lemon, Blackwell Publishing Ltd.)


A. Hepatitis C virus research

The cohort of Irish women infected in 1977 with HCV contaminated anti-D provide an important opportunity for analysis of host genetic and immunological factors in HCV. As an integral part of the Liver Research Programme, a consortium of consultant hepatologists and researchers from all over Ireland was established to direct successful research into different aspects of HCV in the Irish cohort. A major highlight was the award in 2007 of a HRB Translational Programme Grant  ‘Immune targeting strategies: improving the response rate to IFN-alpha/ribavirin therapy in chronic Hepatitis C Virus infection’. This project aims to improve the response rate to Interferon therapy in HCV infected patients and is a collaboration between Profs. John Hegarty (SVUH), Cliona O’Farrelly (now Professor of Comparative Immunology at Trinity College Dublin) Dermot Kelleher, Suzanne Norris and Aideen Long (SJH). Also new MD students of SVUH will be joining this collaboration and working with immunology research assistants between SVUH and TCD.


 
Specific HCV research projects include:

a. Analysis of how HCV destroys important proteins of the immune response, to provide clinicians with a predictive tool of response and identify potential targets of future therapy

b. Investigating the potential use of Growth Factors as enhancers of current therapies

c. Study the effect of Suppressor of cytokine signalling (SOCS) proteins upon HCV progression and response to therapy

 

 

 

 

 

Refs:

Phenotypic and Functional Changes of Cytotoxic CD56pos NT Cells Determine Outcome of Acute HCV Infection. Golden-Mason L, Castelblanco N, O’Farrelly C, Rosen HR. J. Virol. 2007. 81(17):9292-8. PMID 17553896.

The hepatitis C envelope 2 protein inhibits LFA-1-transduced protein kinase C signaling for T-lymphocyte migration. Y. Volkov, A. Long, L. Golden-Mason, S. Abrignani, C. O’Farrelly, A. Murphy, D. Kelleher.  Gastroenterology. 2006. 130(2):482-92. PMID 16472601.

 Reconstitution of Hepatitis C virus-specific T-cell-mediated immunity after liver transplantation. S.J. Weston, R. Leistikow, K. Rajender Reddy, M. Torres, A.M. Wertheimer, D.M. Lewinsohn, S. Chou, M. P. Davey, C. Corless, C. O’Farrelly, D.R. Nelson, H.R. Rosen. Hepatology. 2005. 41(1) 72-81. PMID 15619226

Expansion of Innate CD5pos B Cells Expressing High Levels of CD81 in HCV Infected Liver MP Curry, L Golden-Mason , DG Doherty, S Norris,  M Duffy, N Nolan, W Hall, JE Hegarty*, C O’Farrelly* J. Hepatol 2003; 38:642-650 PMID 12713876

Decrease in hepatic CD56+ T cells and Va24+ natural killer T cells in chronic Hepatitis C viral infection. T. Deignan, M.P. Curry, D.G. Doherty, L. Golden-Mason, Y. Volkov, S. Norris, N. Nolan, O. Traynor, G. McEntee, J.E. Hegarty*, C. O’Farrelly*. J Hepatol 2002; 37:101-8 PMID 12076868

Expansion of peripheral blood CD5+ B cells is associated with mild disease in chronic Hepatitis C virus infection.  M. Curry, L. Golden-Mason, N. Nolan, N. Parfrey, J. Hegarty*, C. O’Farrelly*.  J Hepatol 2000;32:121-125. PMID 10673076

B. Liver Transplantation

The effect of hypoxia on reactive oxygen species (ROS) and other inflammatory changes in donor liver during harvest.

Refs:

Lower expression of Nrf2 mRNA in older donor livers: a possible contributor to increased ischemia-reperfusion injury?  Zaman M, Leonard M, Ryan E, Nolan N,  Hoti E, Maguire D, Mulcahy H, Traynor O, Taylor C, Hegarty J, Geoghegan J,  O'Farrelly C. Transplantation. 2007. 2007.  84(10):1272-8.

Reconstitution of Hepatitis C virus-specific T-cell-mediated immunity after liver transplantation. S.J. Weston, R. Leistikow, K. Rajender Reddy, M. Torres, A.M. Wertheimer, D.M. Lewinsohn, S. Chou, M. P. Davey, C. Corless, C. O’Farrelly, D.R. Nelson, H.R. Rosen. Hepatology. 2005. 41(1) 72-81. PMID 15619226

Nitric Oxide in Early Ischaemia Reperfusion Injury During Human Orthotopic Liver Transplantation  R. Varadarajan, L. Golden-Mason, L. Young, P. McLoughlin, N. Nolan, G. McEntee, O. Traynor, J. Geoghegan, J. Hegarty*, C. O’Farrelly*  Transplantation 2004 July 27;78(2):250-6 PMID 15280686

Localisation of T and B Lymphocytes in Histologically Normal Adult Human Donor Liver F. Smith, L. Golden-Mason, T. Deignan, S. Norris, N.Nolan, O.Traynor, G.McEntee, J.Hegarty*, C.O’Farrelly* J. Hepato-Gastro 2003; Sep-Oct:50(53):1311-5 PMID 14571725

Changes in peripheral blood double-negative T-lymphocyte (CD3+ CD4- CD8) populations associated with acute cellular rejection after liver transplantation.  O. Crosbie, P. Costello, C. O’Farrelly, J. Hegarty.  Liver Transpl Surg 1998;4:141-145. PMID 9516566

Donor type microchimerism is an infrequent event following liver transplantation and is not associated with graft acceptance.  S. Norris, M. Lawlor, S. McCann, G. McEntee, O. Traynor, J. Hegarty, C. O’Farrelly. Hepatology 1997;26:848-852. PMID 9328303


C. Liver Cancer

The role of immune cells and immunoregulatory cytokines in liver malignancy.

Refs:

CD1 expression and CD1-restricted T cell activity in normal and tumour-bearing human liver. Kenna T, O’Brien  M, Exley M,  Porcelli S,  Hegarty J, O’Farrelly C, Doherty DG.  Cancer Immunol Immunother 2007.  56, (4) 563 – 572.  PMID 16924493

Changes in hepatic immunoregulatory cytokines in patients with metastatic colorectal carcinoma: implications for hepatic anti-tumour immunity. AM Kelly, L. Golden-Mason, O. Traynor , J. Geoghegan, G. McEntee, J. Hegarty, C. O’Farrelly. Cytokine. 2006. 35 (3-4):171-179 PMID 16971136

Liver Immunity and Tumour Surveillance Canning C, O’Brien M, Hegarty J, O’Farrelly C  Immunology Letters 2006, 107 (2) 83-88.  PMID 17101177

Distinct subpopulations of gamma delta T Cells are present in normal and tumor-bearing human liver. T. Kenna, L. Golden-Mason, S. Norris, J.E. Hegarty*, C. O’Farrelly*, D. Doherty Clin Immunol 2004 Oct; 113(1):56-63 PMID 15380530

Interleukin 12 (IL-12) is increased in tumour-bearing liver and expands CD8 (+) and CD56 (+) T cells in vitro but not in vivo. A. Kelly, L.Golden-Mason,G. McEntee, O. Traynor, J.Hegarty*, D.Doherty, C. O’Farrelly* Cytokine 2004 Mar 21;25(6):273-82   PMID 15036243

NKT cells from normal and tumor-bearing human livers are phenotypica and functionally distinct from murine NKT cells. T. Kenna, L. Golden-Mason, SA Porcelli, Y. Koezuka, JE Hegarty*, C. O’Farrelly*, DG Doherty J. Immunol. 2003 Aug 15;171(4):1775-9. PMID 12902477

Selective reduction of natural killer cells and T cells expressing inhibitory receptors for MHC class 1 in the livers of patients with hepatic malignancy.  S. Norris, D.G. Doherty, M. Curry, G. McEntee, O. Traynor, J.E. Hegarty*, C. O’Farrelly* Cancer Immunology Immunotherapy 2003; 52:53-58 PMID 12536240

Differential expression of lymphoid and myeloid markers on differentiating hematopoietic stem cells in normal and tumor bearing adult human liver.  L. Golden-Mason, M. Curry, N. Nolan, O. Traynor, G. McEntee, J. Kelly, J. Hegarty*, C. O’Farrelly*.  Hepatology 2000; 31:1251-1256. PMID 10827150

Contact:

 deirdre.oriordan@svuh.ie

or

cliona.ofarrelly@tcd.ie