Liver Fibrosis Clinical Trial
Official title:
The Employing of the Bio-Hep-B PreS1/PreS2/S Hepatitis B Virus (HBV) Vaccine in New Born Babies From HBV Positive Palestinian Mothers
Impaired activity of Natural Killer (NK) cells has been proposed as a mechanism contributing to viral persistence in Hepatitis C Virus (HCV) infection. NK cells display anti-fibrotic activities by killing activated hepatic stellate cells (HSCs) that have lost the self-recognition marker; Major Histocompatibility (MHC) class I. Determining the down-expressed genes on NK cells necessary for their anti-fibrotic activity was never studied previously. This will allow us to study their role fully in phagocytosis process as well as their interaction of HSCs and therefore manipulating these genes using molecular techniques. Exploring the cellular functions of these genes will highlight their involvement in the progression of liver fibrosis and could be used as a therapeutic tool for preventing the disease.
Lymphocyte/Hepatic stellate cells (HSCs) interactions via adhesion and phagocytosis are
mediated as well as affected among others by Leptin, Endocannabinoids (CB) receptors,
adiponectin, progesterone as well as by number of CD8 and NK related adhesion/phagocytosis
candidate genes. Those pathways may explain the impaired activity of NK cells in Hepatitis C
Virus (HCV)cirrhotic cases.
In this perspective, we propose the following specific aims:
1. To confirm by repeated gene arrays the pro/anti-fibrotic genes expressed by NK and CD8
lymphocyte-subsets in human healthy volunteers and patients with HCV cirrhosis. Then to
explore the same issue of lymphocyte gene array (NK and CD8 cells) in naïve and carbon
tetrachloride fibrosis model in mice. Then to support results by the Real Time PCR and
conduct bio-informatics assessments of results.
2. Evaluate the role of Leptin, CB receptors and adiponectin in the lymphocyte/HSCs
phagocytosis process. This would be tested both by in-vitro and in-vivo settings using
cell cultures and knock-out mice (CB2-/-, Adiponectin-/- and leptin-/-Ob/Ob). The use
of lymphocyte adoptive transfer model with immune manipulations will guide us for a
specific functional role of each target gene in the specific lymphocyte subset.
3. To evaluate how lymphocyte/HSC phagocytosis process affected by other CD8 and NK
related gene candidates extrapolated from the results of earlier aims (see preliminary
data). Suggested genes are including: Immune synapse genes (CHST13 and NLGN4X) to
obtain the expected anti-fibrotic response. Genes with HSCs phagocytotic activity that
is providing possible pathways for the HCV related escape from the expected
anti-fibrotic response and eventually pro- fibrotic consequences (AIF1, CHST13, hnRPL).
Killer cell lectin-like receptor subfamily C, member 2 (NKG2C; CD159c) is down
expressed over HCV related CD8 cells suggesting a decrease of HSCs killing by the CD8
cells. Progestin & adipoQ receptor family member IV (PAQR4): Progesterone and adipoQ
receptors are down-expressed over HCV related CD8 cells. Adiponectin is anti-fibrogenic
mediator and is a candidate as PAQR4 ligand. When PAQR4 receptor is down- regulated in
CD8 cells, it is suggested that this would be a mechanism for immune impairment. Also,
Moreover, Progesterone and adipoQ receptors down- expression is supporting our mice
animal model results that pregnancy caused progression of hepatic fibrogenesis
associated with increased CD8 subsets and NK-T cells. We are going to evaluate the
specific effect in the phagocytosis process.
4. To evaluate if HCV by itself or HCV related proteins are directly responsible for the
NK related impairment. Transgenic mice for the HCV envelop proteins will be used to
assess alterations of lymphocyte subsets and phagocytosis ability.
The expected results will extend the knowledge of hepatic fibrogenesis in particular but may
provide more application in general immunology. Therefore, expected results will be
potentially a new target for anti-fibrotic designs and possibly in other medical conditions.
Not only liver cirrhosis will be potentially prevented following anti-fibrotic therapies but
also the hepatocellular carcinoma
;
Allocation: Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Factorial Assignment, Masking: Single Blind (Investigator), Primary Purpose: Prevention
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