The Role of FGL2-FcgammaRIIB Inhibitory Pathway in Human Viral Hepatitis
Condition: Chronic Hepatitis C Infection
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis, Viral, Human; Hepatitis
Study type: Observational

Summary: 
      Viral hepatitis is a serious world health problem affecting over 1 billion people worldwide.
      Presently the lack of highly effective treatments results in many patients requiring liver
      transplantation or death. The investigators have defined the role of a unique molecule FGL2
      and its receptor fc-gammaR and its role in the pathogenesis of both experimental and human
      hepatitis. The studies proposed in the present proposal will test the hypothesis that
      measuring levels of fgl2 in plasma will identify individuals that will go on to develop
      chronic disease and inhibition of binding of fgl2 to its receptor will allow the host with
      both acute and chronic disease to develop an appropriate immune response and clear the virus.
      The studies will provide rationale for generation of new therapies to improve the treatment
      of patients with acute and chronic viral hepatitis by targeting fgl2.
    

Detailed description: 
      Hepatitis C Virus (HCV) infection affects more than 200 million individuals worldwide. Only a
      fraction of infected individuals clear the virus, whereas the majority (70%) develops chronic
      infection. The current standard of care, pegylated interferon/ ribavirin (pegIFN/rib) is
      effective in only 50% of patients. Patients who fail anti-viral therapy gradually progress to
      end-stage liver disease and hepatocellular cancer; which can only be cured by a liver
      transplant. The reasons for treatment failure are unclear but involve both viral and host
      factors. One significant factor may be impaired T cell function. Chronic HCV infection is
      associated with functionally impaired or exhausted cytotoxic T lymphocytes (CTLs), with
      decreased anti-viral cytokine production, cytotoxicity and proliferative capacity. The
      investigators recently showed that many patients who fail treatment have elevated frequencies
      of CD4+CD25+Foxp3+regulatory T cells (Tregs) producing the novel fibrinogen-like-protein 2
      (FGL2/fibroleukin) which appears to impair HCV specific immune responses. Binding of FGL2 to
      the FcγRIIB receptor leads to inhibition of dendritic cell (DC) maturation, B cell apoptosis
      and inhibition of development of effective CD4+and CD8+T and B cell anti-viral responses. In
      HCV, increased levels of secreted FGL2 may suppress anti-viral immune responses and promote
      disease progression.

      Hypothesis: HCV suppresses innate and adaptive anti-viral immune responses through the
      FGL2-FcγRIIB inhibitory pathway. Inhibition of this pathway will restore effective
      virus-specific immunity and lead to successful viral eradication.

      Significance: These studies will establish the importance of FGL2-FcγRIIB inhibitory pathway
      in the pathogenesis of HCV chronic infection and provide a novel therapeutic approach to
      improve virus eradication and long term patient outcomes.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients being followed by hepatologists and considering treatment of Hepatitis C vs
        controls derived from potential live liver donors (for transplant)
      
Keywords: HCV; T regulatory cells (Tregs); FGL2