Ignite Creation Date:
2024-05-05 @ 10:17 AM
Last Modification Date:
2024-10-26 @ 9:05 AM
Study NCT ID:
NCT00007371
Status:
COMPLETED
Last Update Posted:
2016-09-26
First Post:
2000-12-19
Brief Title:
Hepatitis C in Clinically Discordant Hemophilic Siblings
Sponsor:
University of North Carolina Chapel Hill
Organization:
University of North Carolina Chapel Hill
Study Overview
Official Title:
Hepatitis C in Clinically Discordant Hemophilic Siblings
Status:
COMPLETED
Status Verified Date:
2005-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
To define the natural history immunologic and genetic factors that influence the clinical outcome of hepatitis C in a cohort of hemophilic siblings
Detailed Description:
BACKGROUND
The clinical spectrum of hepatitis C is variable and the factors responsible for these divergent outcomes with chronic hepatitis C infection remain unknown Dr Fried and his colleagues are studying a cohort of hemophilic siblings infected with hepatitis C to define the natural history immunologic and genetic factors that influence its clinical outcome Patients with hemophilia have a prevalence rate of hepatitis C as high as 90 percent The sex-linked pattern of inheritance of hemophilia allows them to identify a cohort of siblings both of who have been infected with hepatitis C Hemophilic siblings are an attractive population to study because 1 They are all males 2 Siblings are relatively close in age 3 The mode of HCV acquisition is identical 4 The age at acquisition of hepatitis C is similar 5 The date of acquisition can be confidently estimated upon their factor replacement history 6 Hemophilic sibs share significant amounts of genetic material
The study is in response to a Request for Applications entitled Hepatitis C Natural History Pathogenesis Therapy and Prevention issued by the National Institute of Diabetes and Digestive and Kidney Diseases
DESIGN NARRATIVE
Hemophilic siblings with hepatitis C undergo a detailed clinical evaluation to stage their liver disease and to identify sibling pairs with clinically andor histologically discordant levels of disease activity These siblings pairs are further studied to define antigen recognition patterns of lymphocyte cells including peripheral CD8 plus cytotoxic T lymphocytes CTL and CD4 plus cells and determine their functional significance Using peripheral blood mononuclear cells CD8 plus cells are assayed for CTL activity against three overlapping vacciniahepatitis C virus HCV constructs covering the entire HCV genome followed by fine cloning to identify HCV-specific CTL epitopes Peripheral CD4 plus cells are tested for their ability to proliferate to HCV antigens Using stimulation index Drs Fried and colleagues are quantitating the presence and magnitude of this response They are also trying to identify immunodominant regions targeted by cytotoxic T cells using HLA class I matched hemophilic siblings Finally they are identifying specific host genes that are preferentially expressed or repressed in patients with delayed progression of their HCV disease They are quantitating the expression of mRNAs encoding host antiviral defense and immunoregulatory elements in peripheral blood mononuclear cells PBMCs and liver tissue from sibling pairs that have discordant chronic hepatitis C using mRNA libraries that are screened by high density oligonucleotide arrays The expression levels of these genes including but not limited to interferon alpha beta and gamma IRF-1 and IRF-2 interferon induced protein kinase the cellular protein activator of PKR PACT RNase L interferon-inducible RNA-specific adenosine deaminase a ribonuclease specific for inosine- containing RNA chemokine receptors CCR1 CCR3 CCR5 and their signal transduction elements 2-5-oligoadenylate synthetase tumor necrosis factor FAS receptor signal transduction components of these antiviral pathways and both type 1 and 2 cytokines are correlated with delayed progression and diminished pathogenesis in paired hemophilic siblings
The clinical spectrum of hepatitis C is variable and the factors responsible for these divergent outcomes with chronic hepatitis C infection remain unknown Dr Fried and his colleagues are studying a cohort of hemophilic siblings infected with hepatitis C to define the natural history immunologic and genetic factors that influence its clinical outcome Patients with hemophilia have a prevalence rate of hepatitis C as high as 90 percent The sex-linked pattern of inheritance of hemophilia allows them to identify a cohort of siblings both of who have been infected with hepatitis C Hemophilic siblings are an attractive population to study because 1 They are all males 2 Siblings are relatively close in age 3 The mode of HCV acquisition is identical 4 The age at acquisition of hepatitis C is similar 5 The date of acquisition can be confidently estimated upon their factor replacement history 6 Hemophilic sibs share significant amounts of genetic material
The study is in response to a Request for Applications entitled Hepatitis C Natural History Pathogenesis Therapy and Prevention issued by the National Institute of Diabetes and Digestive and Kidney Diseases
DESIGN NARRATIVE
Hemophilic siblings with hepatitis C undergo a detailed clinical evaluation to stage their liver disease and to identify sibling pairs with clinically andor histologically discordant levels of disease activity These siblings pairs are further studied to define antigen recognition patterns of lymphocyte cells including peripheral CD8 plus cytotoxic T lymphocytes CTL and CD4 plus cells and determine their functional significance Using peripheral blood mononuclear cells CD8 plus cells are assayed for CTL activity against three overlapping vacciniahepatitis C virus HCV constructs covering the entire HCV genome followed by fine cloning to identify HCV-specific CTL epitopes Peripheral CD4 plus cells are tested for their ability to proliferate to HCV antigens Using stimulation index Drs Fried and colleagues are quantitating the presence and magnitude of this response They are also trying to identify immunodominant regions targeted by cytotoxic T cells using HLA class I matched hemophilic siblings Finally they are identifying specific host genes that are preferentially expressed or repressed in patients with delayed progression of their HCV disease They are quantitating the expression of mRNAs encoding host antiviral defense and immunoregulatory elements in peripheral blood mononuclear cells PBMCs and liver tissue from sibling pairs that have discordant chronic hepatitis C using mRNA libraries that are screened by high density oligonucleotide arrays The expression levels of these genes including but not limited to interferon alpha beta and gamma IRF-1 and IRF-2 interferon induced protein kinase the cellular protein activator of PKR PACT RNase L interferon-inducible RNA-specific adenosine deaminase a ribonuclease specific for inosine- containing RNA chemokine receptors CCR1 CCR3 CCR5 and their signal transduction elements 2-5-oligoadenylate synthetase tumor necrosis factor FAS receptor signal transduction components of these antiviral pathways and both type 1 and 2 cytokines are correlated with delayed progression and diminished pathogenesis in paired hemophilic siblings
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R01HL064817 | NIH | None | httpsreporternihgovquickSearchR01HL064817 |