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Commentary
authors demonstrated a poor translational
efficacy of the B cell specific IRES-es in
liver-derived hepatoma Huh7 cells and
primary human hepatocytes but not in B
cell lines, such as Raji and Daudi. They
also observed a comparable translational
efficiency of IRES variants found in
different patients in the same compartment (B cells vs. plasma) and a greater
translational independence of the B cell
specific IRES-es from a potent transacting factor (lupus antigen) than those
from plasma genomes. Taken together,
the data suggest that HCV variants
residing in B cells differ in their translational capacity from those occurring in
plasma, which should predominantly
originate from infected livers, and that
they are better adapted to propagate in B
cells than hepatocytes. Despite limitations posed by the translation approach
used, since only the IRES sequences
alone out of the context of the complete
virus genome were investigated, the
study provides further support for the
existence of extrahepatic HCV replication. Propagation of HCV in the immune
system may have implications both for
spreading virus variants potentially
escaping immune and antiviral agent
elimination and by modifying immune
cell functions in ways promoting virus
persistence.
Provenance and peer review Commissioned; not
externally peer reviewed.
Correspondence to Fabio Marra, Dipartimento di
Medicina Interna, Viale Morgagni, 85, Florence I-50134,
Italy; [email protected]
868
6.
7.
Gut 2010;59:867e868.
doi:10.1136/gut.2010.210054
8.
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Pham TNQ, Coffin CS, Michalak TI. Occult hepatitis
C virus infection: what does it mean? Liver Intl
2010;30:502e11.
Blackard JT, Kemmer N, Sherman KE. Extrahepatic
replication of HCV: insights into clinical manifestations
and biological consequences. Hepatology
2006;44:15e22.
Zignego AL, Giannini C, Monti M, et al. Hepatitis
C virus lymphotropism: lessons from a decade of
studies. Digest Liver Dis 2007;39(1 Suppl):
S38e45.
Fabio Marra, Francesco Annunziato
Dipartimento di Medicina Interna and Center for
Research, Transfer and Higher Education DenoTHE,
University of Florence, Florence, Italy
5.
Competing interests None.
Immunomodulation: a new
approach to the therapy of
cirrhosis?
Liver cirrhosis is a leading cause of
mortality in Western countries and the
major risk factor for the development of
hepatocellular carcinoma, a difficult to
treat malignancy with a poor prognosis.
In recent years, the management of
cirrhotic patients has considerably
improved due to better ability to deal with
complications such as portal hypertensive
bleeding, hepatorenal syndrome and
hepatocellular carcinoma. Unless the
causal agent is removed, no therapies are
currently available to slow down the
progressive worsening of hepatic function
after the development of cirrhosis, and
liver transplantation remains the only
approach that has an impact in the long
4.
term. Considerable advancements have
also been made in the understanding of
the pathophysiology of hepatic fibrosis,
and the pivotal role played by hepatic
inflammation has been clearly defined.
Inflammation is part of the tissue ‘wound
healing’ response, and leucocyte populations differentially modulate the process
of fibrogenesis, that leads to the development of cirrhosis.1 Monocytes and activated macrophages contribute to the
development and progression of fibrosis
via expression of numerous cytokines,
such as platelet-derived growth factor and
transforming growth factor-b1, or generation of reactive oxygen intermediates.
The role of T cells is more complex, and
the available data indicate that a Th1polarised response is associated with
reduced deposition of extracellular matrix,
partly mediated by secretion of interferon
(IFN)-g, whereas Th2-related cytokines
such as interleukin (IL)-4 and IL-13 cause
a more rapid progression of fibrosis.1 Once
9.
10.
Laporte J, Bain C, Maurel O, et al. Differential
distribution and internal translation efficiency of
hepatitis C virus quasispecies present in dendritic and
liver cells. Blood 2003;101:52e7.
Di Liberto G, Roque-Afonso AM, Kara R, et al.
Clinical and therapeutic implications of hepatitis
C virus compartmentalization. Gastroenterology
2006;131:76e84.
Sung VM-H, Shimodaira S, Doughty AL, et al.
Establishemnt of B-cell lymphoma cell lines
persistently infected with hepatitis C virus in vivo and
in vitro: the apoptotic effects of virus infection. J Virol
2003:77:2134e46.
Shimizu YK, Iwamoto A, Hijikata M, et al. Evidence
for in vitro replication of hepatitis C virus genome in
a human T-cell line. Proc Natl Acad Sci USA
1992;89:5477e81.
Laskus T, Radkowski M, Jablonska M, et al. Human
immunodeficiency virus facilitates infection/
replication of hepatitis C virus in naive human
macrophages. Blood 2004;103:2854e3859.
MacParland SA, Pham TNQ, Guy CS, et al.
Hepatitis C persisting after clinically apparent
sustained virological response to antiviral therapy
retains infectivity in vitro. Hepatology
2009;49:1431e41.
Durand T, Di Liberto G, Colman H, et al. Occult
infection of peripheral B-cells by hepatitis C variants
which have low translational efficiency in cultured
hepatocytes. Gut 2010;59:934e42.
cirrhosis has been established, the presence of inflammation and the related
hyperproduction of cytokines, including
tumour necrosis factor (TNF)-a, in the
splanchnic district and in the systemic
circulation, is responsible for the worsening of portal hypertension and appearance of hyperdynamic circulation.2
In the current issue of Gut, Albillos et al3
(see page 943) have utilised a novel
experimental approach for the treatment
of cirrhosis, investigating the effects of
AM3, a naturally derived modulator of
innate and adaptive immunity, in rats
with cirrhosis caused by ligation of the
common bile duct. AM3 exerted multiple
effects on both circulating and liver-infiltrating monocytes, that can be recapitulated as a reduction of their number and
activation state, and limitation of their
ability to produce TNF. The T cell
component was also affected, with
a reduced number of total and activated T
cells and a lower ability to produce IFN-g
on stimulation. Moreover, the number of
circulating and intrahepatic NK cells was
reduced, together with their ability to
produce IFN-g. These immunological
changes induced by AM3 were accompanied by a reduction of the amount of
fibrotic tissue and lower expression of
genes involved in fibrogenesis. Of note,
the beneficial effects of AM3 also extended
to the features of advanced liver disease. In
Gut July 2010 Vol 59 No 7
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Commentary
fact, treatment with the immune modulator resulted in a significant reduction in
portal pressure and improved parameters
of systemic circulatory dysfunction.
The results of this carefully conducted
study demonstrate that interference with
the processes that regulate activation and
function of immune cells may improve the
advanced stages of experimental cirrhosis.
This original observation confirms that
an ‘inflammatory thread’ is present
throughout the course of chronic liver
disease, leading from chronic hepatitis to
cirrhosis, portal hypertension and finally to
haemodynamic alterations typical of end
stage liver disease. More importantly, the
results provided by Albillos et al3 provide
new perspectives in the search for more
effective treatments for this debilitating
and severe disease. Moreover, it is of relevance that the experimental protocol was
designed to provide information potentially translatable to the clinical setting,
that is initiating the therapy with AM3
once cirrhosis was established, and not as
a ‘pre-emptive’ treatment.
Based on the role of inflammation in the
process of chronic liver disease, interference
with the immune system appears an
attractive strategy. Until now, this has been
mostly conducted with the use of immunosuppressive drugs, which are the current
standard of care in autoimmune hepatitis,
but are generally not indicated in chronic
liver diseases due to other aetiologies. More
modern drugs have been developed over the
past 10 years, that act by blocking the
biological activity of molecules, such as
TNF-a, generated during an inflammatory
reaction. However, clinical trials of inhibitors of TNF or other proinflammatory
cytokines, such as IL-1, IL-6, IL-12 or IL-17,
clearly demonstrated that administration
of these compounds is accompanied by
a series of adverse events, including severe
infections.4 As bacterial infections represent an important cause of death in
patients with cirrhosis, drugs interfering
with the immune system should be used
with great caution in this group of
patients.5 Thus, as reported in the study by
Albillos et al,3 the ability of AM3 to regulate
cytokine expression and immune cell
function without behaving as an immunosuppressive agent, would make this
compound an appealing therapeutic agent.
However, this conclusion will need further
experimental data to be fully supported. In
fact, the immunomodulatory versus
immunosuppressive action of AM3 was
mostly based on the lack of effects on TNFa production by activated circulating T
cells, whereas no data on the ability of liverGut July 2010 Vol 59 No 7
infiltrating T lymphocytes to produce
TNF-a were reported. Moreover, it should
be pointed out that circulating TNF-a and
TNF expression by activated monocytes,
were markedly reduced by AM3 treatment,
as well as IFN-g production by both circulating and liver-infiltrating T cells. Accordingly, although comparable bacterial
translocation and endotoxin levels were
observed, when comparing AM3 treated and
untreated cirrhotic rats no differences in
mortality were shown. Therefore, caution is
needed before the hypothesis that AM3 is an
immunomodulator that can overcome
problems occurring with immunosuppressors is fully accepted. Thus, additional
studies are mandatory to better define the
profile of this immunomodulator in chronic
liver diseases, and the experimental model of
cirrhosis reported in this study3 appears to
be a very good starting point.
Another aspect that warrants additional
investigation is the translatability of these
findings to a situation where the immune
system is implicated in the control of the
primary disease, as in chronic viral hepatitis. In fact, although bile duct ligation is
an accepted model for the study of fibrogenesis and cirrhosis, it is poorly representative of liver diseases that are most
commonly encountered in clinical practice. Along these lines, the impact of AM3
on liver disease in humans needs to be
carefully assessed in the light of previous
studies indicating that in certain conditions this compound may have immunostimulatory activities.6
A very interesting aspect of the work of
Albillos et al3 is the inhibition of fibrogenesis in rats receiving AM3. The antifibrogenic actions of AM3 occurred despite
the reduction of the number of liver-infiltrating NK cells and IFN-g expression,
conditions that have been associated, at
least in rodents, with a potent antifibrotic
effect.7 An intriguing aspect, considering
the observed reduction of TNF-a expression
by monocytes, is the possible relation with
a recent study demonstrating that expression of TNF-a by hepatic dendritic cells is
a driving mechanism for the development
of fibrosis.8 AM3 has been recently
demonstrated to modulate the biology of
dendritic cells,9 and although dendritic cells
were not investigated in the study of
Albillos et al,3 the possibility that AM3
provides antifibrogenic signals via this
pathway deserves additional investigation.
One additional point of interest is the
inhibition of bile duct epithelial cell proliferation by AM3 treatment, confirmed by
the lower levels of alkaline phosphatase in
treated rats. Bile duct proliferation often
occurs in a proinflammatory environment,
and cholangiocytes have been shown to
express several factors that promote proliferation and matrix expression by hepatic
myofibroblasts, that are also directionally
recruited to areas of bile duct proliferation.10 As newly formed bile ducts have
been associated with a faster progression of
fibrosis in human diseases, including steatohepatitis, the ability of AM3 to modulate
the cross-talk between inflammatory cells
and proliferating cholangiocytes represents
another translatable finding highlighted
by the study by Albillos et al.3
In conclusion, data obtained in recent
years have demonstrated that the hepatic
repair process and the severity of cirrhotic
complications are tightly regulated by
inflammation. The work reported in this
issue of Gut represents an excellent
starting point to develop further studies,
in order to understand whether an
immunomodulatory strategy with AM3,
or other compounds, may be of benefit for
the treatment of patients with progressive
chronic liver diseases.
Competing interests None.
Provenance and peer review Commissioned; not
externally peer reviewed.
Gut 2010;59:868e869.
doi:10.1136/gut.2009.203109
REFERENCES
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Iwakiri Y, Groszmann RJ. The hyperdynamic
circulation of chronic liver diseases: from the patient
to the molecule. Hepatology 2006;43:S121e31.
Albillos A, Nieto M, Ubeda M, et al. The biological
response modifier AM3 attenuates the inflammatory
cell response and hepatic fibrosis in rats with biliary
cirrhosis. Gut 2010;57:943e52.
Hochberg MC, Lebwohl MG, Plevy SE, et al. The
benefit/risk profile of TNF-blocking agents: findings of
a consensus panel. Semin Arthritis Rheum
2005;34:819e36.
Wong F, Bernardi M, Balk R, et al. Sepsis in
cirrhosis: report on the 7th meeting of the
International Ascites Club. Gut 2005; 54:718e25.
Prieto A, Reyes E, Bernstein ED, et al. Defective
natural killer and phagocytic activities in chronic
obstructive pulmonary disease are restored by
glycophosphopeptical (inmunoferon). Am J Respir Crit
Care Med 2001;163:1578e83.
Gao B, Jeong WI, Tian Z. Liver: An organ with
predominant innate immunity. Hepatology
2008;47:729e36.
Connolly MK, Bedrosian AS, Mallen-St Clair J, et al.
In liver fibrosis, dendritic cells govern hepatic
inflammation in mice via TNF-alpha. J Clin Invest
2009;119:3213e25.
Martin-Vilchez S, Molina-Jimenez F,
Alonso-Lebrero JL, et al. AM3, a natural
glycoconjugate, induces the functional maturation
of human dendritic cells. Br J Pharmacol
2008;154:698e708.
Glaser SS, Gaudio E, Miller T, et al. Cholangiocyte
proliferation and liver fibrosis. Expert Rev Mol Med
2009;11:e7.
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Downloaded from gut.bmj.com on March 28, 2011 - Published by group.bmj.com
Immunomodulation: a new approach to the
therapy of cirrhosis?
Fabio Marra and Francesco Annunziato
Gut 2010 59: 868-869
doi: 10.1136/gut.2009.203109
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