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  • Final Report Summary - LIVER IVM AND HBV (Imaging liver immunopathology by intravital microscopy (IVM): a new approach to study the pathogenesis of hepatitis B virus (HBV) infection.)

LIVER IVM AND HBV Report Summary

Project ID: 250219
Funded under: FP7-IDEAS-ERC
Country: Italy

Final Report Summary - LIVER IVM AND HBV (Imaging liver immunopathology by intravital microscopy (IVM): a new approach to study the pathogenesis of hepatitis B virus (HBV) infection.)

HBV causes acute and chronic necroinflammatory liver diseases of varying severity. It is generally acknowledged that hepatocellular HBV infection is noncytopathic, that it does not trigger innate immune responses readily measurable in vivo, and that robust, polyclonal and multispecific CD4 and CD8 T cell responses and neutralizing antibody responses contribute to the resolution of HBV infection. HBV persists in the majority of neonatal/perinatal infections and secondarily triggers an indolent low grade chronic necroinflammatory liver disease that can progress to cirrhosis and hepatocellular carcinoma (HCC). Vaccines that elicit neutralizing antibodies efficiently prevent de novo HBV infection, but have no therapeutic potential for the ~ 240 million people that are persistently infected with this virus worldwide. Therapy for these individuals mainly relies on antiviral drugs that suppress virus production but do not eradicate HBV from the liver, requiring lifelong treatment.

This project aimed at further elucidating the pathogenesis of HBV infection with the ultimate hope that this knowledge may ease the design of new therapeutic strategies to terminate persistent infection and its attendant costs and complications.
Elucidation of HBV pathogenesis mainly involved a through characterization of 3 cell types (effector CD8 T cells [CD8 TE], platelets and Kupffer cells) whose role and function had remained incompletely understood and it relied on improved or novel mouse models of acute or chronic hepatitis B and on advanced static and dynamic imaging platforms based on epifluorescence and multi-photon intravital microscopy, 3D confocal fluorescence microscopy, correlative light and electron tomography and 7 Tesla MRI. Thanks to these resources we could show that circulating CD8 TE initially arrest in liver sinusoids by docking onto sinusoidal endothelial cell-adherent platelets. CD8 TE then crawl intrasinusoidally and probe underlying hepatocytes by extending filopodia-like protrusions through sinusoidal fenestrae, whereupon they recognize hepatocellular antigen, produce IFN-γ and kill HBV-replicating hepatocytes from within the intravascular space. Notably, hepatocellular Ag recognition by CD8 TE is inhibited by the processes of sinusoidal defenestration (i.e. the reduction in number and size of sinusoidal fenestrae) and sinusoidal capillarization (i.e. the deposition of extracellular matrix underneath the sinusoidal wall), both of which are characteristic of liver fibrosis/cirrhosis. This suggests that CD8 TE might have impaired antigen recognition capacity in fibrotic patients.

That platelets represent key players initiating the pathogenesis of viral hepatitis was also indicated by studies performed in a mouse model of chronic HBV infection where we evaluated mode of action, safety and efficacy of anti-platelet therapies based on aspirin and/or clopidogrel. We showed that daily low-doses of these drugs (identical to those widely used in humans to prevent thrombotic disorders) limited the hepatic accumulation of CD8 TE (which - in contrast to what happens during acute hepatitis - contribute more to liver damage than to viral clearance) and the consequent liver disease, ultimately preventing the development of cirrhosis or HCC and improving overall survival. Anti-platelet therapy, therefore, may represent a novel therapeutic option in patients with chronic HBV infection. Accordingly, it appears that a clinical trial based on these results is about to start in mainland China.

Taking advantage of the same mouse models and imaging approaches abovementioned, we have also recently demonstrated that Kupffer cells, the intravascular liver-resident macrophages, limit disease severity during acute hepatitis by rapidly removing apoptotic hepatocytes that are killed by CD8 TE. Failure to do so results in the secondary necrosis of hepatocytes and abundant liver inflammation. These findings contradicted existing dogmas regarding the role of Kupffer cells in HBV pathogenesis, which considered these cells as important contributors to liver injury.

Reported by

Ospedale San Raffaele
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