Liver-Directed Gamma Interferon Gene Delivery in Chronic Hepatitis C

Shin, Eui‐Cheol; Protzer, Ulrike; Untergasser, Andreas; Feinstone, Stephen M.; Rice, Charles M.; Hasselschwert, Dana L.; Rehermann, Barbara

doi:10.1128/jvi.79.21.13412-13420.2005

Cited by 22 publications

(25 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…31,32,34,35,80,81 In addition, clearance of chronic HCV infection upon IFN-␣ treatment is associated with a shift from a Th2-dominant to a Th1-dominant phenotype. 80,82,83 The importance of Th1-associated cytokines in the clearance of HCV is thought to be due, in part, to their ability to enhance CTL activities, 84 which in turn are associated with viral clearance. 3,10,26,53,54 Thus, the ability of therapeutic regimens to modulate the polarity of the Th cell population may influence treatment outcome.…”

Section: Therapeutically Relevant Concentrations Of Ifns Differentialmentioning

confidence: 99%

Immunomodulatory Activities of IFN-γ1b in Combination with Type I IFN: Implications for the Use of IFN-γ1b in the Treatment of Chronic HCV Infections

Wang¹,

Blatt²,

Seiwert³

2006

Journal of Interferon & Cytokine Research

View full text Add to dashboard Cite

The standard of care for chronic hepatitis C, pegylated interferon-alpha (IFN-alpha) and ribavirin (RBV), causes a sustained virologic response (SVR) in approximately 50% of patients. SVR is correlated with innate and adaptive immune system responses, such as natural killer (NK) cell activation, production of IFN-alpha from immature plasmocytoid dendritic cells (pDC), and polarization of CD4(+) cells to a T helper 1 (Th1) cell phenotype. To examine how these immunologic responses vary with currently available regimens for chronic hepatitis C, cell populations purified from human peripheral blood mononuclear cells (PBMC) were treated with the clinically available combinations of pegylated IFN-alpha2b (PEG-IFN-alpha2b) + RBV, IFN-alphacon1 + RBV, or IFN- alphacon1 + IFN-gamma1b, and activation of cellular immune system components was monitored. The magnitude of NK cell activation depended on regimen, with IFN-alphacon1 + IFN-gamma1b > IFN-alphacon1 + RBV > PEG-IFN- alphaa2b + RBV. The maximum human serum concentrations of IFN-alphacon1 + IFN-gamma1b saturated NK cell activation, whereas the maximum human serum concentrations of IFN-alphacon1 + RBV or PEG-IFN-alpha2b + RBV did not. IFN-gamma1b also enhanced the production of IFN-alpha from immature pDCs, which are the dominant source of IFN-alpha upon viral infection. The rank order for induction of Th1 cell phenotype and repression of Th2 cell phenotype by the cocktails described was identical to that observed for NK cell activation. Additionally, IFN- gamma1b suppressed the ability of the hepatitis C virus (HCV) NS4 protein to enhance monocyte secretion of interleukin- 10 (IL-10), a cytokine whose expression level is correlated with viral persistence. These results suggest that addition of IFN-gamma1b to HCV treatment regimens may provide unique benefits.

show abstract

Section: Therapeutically Relevant Concentrations Of Ifns Differentialmentioning

confidence: 99%

Immunomodulatory Activities of IFN-γ1b in Combination with Type I IFN: Implications for the Use of IFN-γ1b in the Treatment of Chronic HCV Infections

Wang¹,

Blatt²,

Seiwert³

2006

Journal of Interferon & Cytokine Research

View full text Add to dashboard Cite

show abstract

“…However, IFNγ expression is abundant in within the liver, even in chronic HCV, and there is no evidence that the level of expression is related to HCV viral load; indeed, the level of IFNγ expression correlates positively with the degree of inflammation within liver tissue [101; 102]. A recent study examined the effect of IFNγ delivery directly into the liver via a gene therapy vector [103] and observed no effect on viral load. Whether other cytokines that might be produced by HCV-specific T cells play a role in controlling HCV replication awaits further study.…”

Section: T Cells In Acute Hcv Infectionmentioning

confidence: 99%

Immune responses during acute and chronic infection with hepatitis C virus

Ishii

Koziel

2008

Clinical Immunology

View full text Add to dashboard Cite

Hepatitis C virus (HCV) induces persistent infection and causes chronic liver disease in most infected patients. Vigorous HCV-specific CD4+ and CD8+ T cell responses against HCV multiple epitopes are necessary for spontaneous viral clearance during the acute phase, but the virus appears to have multiple strategies to evade these defenses. There are relatively few studies on the role of immune responses during the chronic phase of infection. CD4+ T cell responses appear to protect against liver injury and may be important to clearance during interferon and ribavirin based therapy. Classic cytotoxic T cells (CTL) may primarily damage the liver in chronic HCV, but there may be subpopulations of T cells that protect against liver inflammation. Resolution of these outstanding questions is important to the development of a prophylactic vaccine as well as improving therapeutic options for those with chronic infection.

show abstract

“…To evaluate the effect of IFN-␥ in chronic HCV infection, a unique study tested liver-directed delivery of the IFN-␥ gene in chimpanzees chronically infected with HCV [40]. To ensure liver-specific delivery and expression of the IFN-␥ gene, two different delivery vectors were tested: a recombinant replication-deficient HBV vector with a HBV promoter and a recombinant adenoviral vector with a liver-specific promoter.…”

Section: Cytokinesmentioning

confidence: 99%

Immune-based therapy for chronic hepatitis C

Chang

Shin

2009

Journal of Leukocyte Biology

Self Cite

View full text Add to dashboard Cite

Chronic, persistent HCV infection is a public health issue. It often progresses to life-threatening complications, including liver cirrhosis and hepatocellular carcinoma. The current standard therapy is a combination of pegylated IFN-alpha and ribavirin. This therapy results in a sustained virologic response in only 50% of patients infected with HCV genotype 1 and is often accompanied with substantial side-effects. Therefore, it is imperative to develop novel therapies with higher efficacy and less substantial side-effects. Impaired immune responses to HCV are key features of chronic HCV infection; thus, intervention strategies typically involve boosting the immune responses against HCV. These immune-based therapies for chronic HCV infection include therapeutic vaccines, antagonists of T cell inhibitory factors, anti-HCV neutralizing antibodies, cytokines, and agonists for TLRs. Currently, various types of immune-based therapies are under development that might be used as a monotherapy or in combination with other antiviral drugs for the treatment of chronic HCV infection.

show abstract

Liver-Directed Gamma Interferon Gene Delivery in Chronic Hepatitis C

Abstract: Gamma interferon (IFN-␥

Cited by 22 publications

References 41 publications

Immunomodulatory Activities of IFN-γ1b in Combination with Type I IFN: Implications for the Use of IFN-γ1b in the Treatment of Chronic HCV Infections

Immunomodulatory Activities of IFN-γ1b in Combination with Type I IFN: Implications for the Use of IFN-γ1b in the Treatment of Chronic HCV Infections

Immune responses during acute and chronic infection with hepatitis C virus

Immune-based therapy for chronic hepatitis C

Contact Info

Product

Resources

About