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.
b.
c.
improve patient care
modify current treatments so that more patients respond better
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):171179 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 coordinators, 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 Tlymphocyte 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 V24+ 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 (34):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; 31:12511256. PMID 10827150
Contact: deirdre.oriordan@svuh.ie or cliona.ofarrelly@tcd.ie