Annual Review - St Vincent's University Hospital

St. Vincent’s Healthcare Group Limited - Annual Review 2008
Education and Research Centre
Research Activities
generation of a ‘tolergenic’ dendritic cell phenotype.
These results were published in the Journal ‘Human
Immunology’.
The recombinant canarypox virus ALVAC is being
extensively studied as vaccine vector for the
development of new vaccine strategies against chronic
infectious diseases and cancer. Gene profiling analysis
of human monocyte derived dendritic cells (MDDCs)
upon ALVAC infection (Anke Harenburg, Nicolas Burdin
and Franca Spada, Sanofi Pasteur) demonstrated that
the majority of the genes that were up-regulated by
ALVAC belong to the type I interferon signaling pathway,
this may have important implications for the use of this
vaccine system in patients with suppressed IFN
responses such as those with chronic HCV infection.
These results were published in the Journal ‘Vaccine’.
Effect of Chronic HCV infection on Dendritic Cell
phenotype and function.
However, to exploit DC targeted therapies in patients
with chronic infections such as HCV or cancer we need
to understand how DCs in these patient groups differ
from those of healthy individuals. We have made a
number of interesting discoveries, such as finding that
Dendritic cells of HCV+ patients do not produce IFNalpha
in response to poly(I:C) stimulation. Conversely,
MDDCs from HCV+ patients secrete high levels of the
molecule Osteoprotegerin (OPG) a cytokine that plays
an important role in protecting bone from degradation
by osteoclasts.
We are also evaluating DC numbers and phenotype in
the blood and liver of HCV patients.
Elizabeth J. Ryan, John Hegarty, Cliona O’Farrelly
The characterisation of T cell subsets in normal and
diseased liver
T regulatory cells (CD4+CD25+FoxP3+) that secrete
anti-inflammatory cytokines, such as IL-10 and TGF-β
can prevent effective cellular responses. By carefully
characterising this population in normal and diseased
human liver tissue we aim to determine their importance
in controlling the immune response in the liver. Previous
work in Prof. Kingston Mills’ Laboratory has shown that
Fasciola hepatica infection of mice can lessen the
severity of Experimental Autoimmune Encephalitis
(EAE). We aim to characterise liver T regulatory cells in
this model to determine their role in mediating the
suppression of inflammation.
Eszter Nèmeth, Miriam Brady (TCD), Cliona O’Farrelly,
Kingston Mills (TCD)
How does HCV inhibit IFN-α treatment?
The anti-viral action of IFN-α depends on proteins
within the cell known as the Janus kinases (Jak) and
Signal Transducers and Activators of Transcription (STAT)
that make up the JAK/STAT pathway. Since more than
50% of patients do not respond to IFN-α, we are
investigating how HCV affects this pathway and its antiviral
response.
We have discovered that a number of proteins of the
JAK/STAT pathway, essential for an antiviral response,
are absent in many HCV patients. We have also found
that HCV acts to degrade these proteins, which may
explain the lack of response to therapy. We plan to
determine exactly how this virus destroys such
important proteins and in doing so we hope to provide
clinicians with a predictive tool of response and identify
potential targets of for future therapy.
Nigel Stevenson, Nollaig Bourke, Catherine Keogh,
John Hegarty, Cliona O’ Farrelly, Aideen Long (TCD),
Christine Biron (Brown University), Jim Johnston (Queen’s
University, Belfast), Charlie Rice (Rockefeller University)
What role does Suppressors of cytokine signalling
(SOCS) play in HCV resistance to IFN-α treatment?
IFN-α is a powerful intracellular defence system against
viruses and resistance to it is manifested by a reduced
induction of anti-viral genes. SOCS proteins control
cytokine signalling and have been documented to
regulate IFN-α signalling and be triggered by HCV
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