More than 250 million people worldwide are affected by chronic hepatitis B, one of the major risk factors for liver cancer. In these patients, the immune system fails to eradicate the infection and the HBV virus keeps replicating and striving inside liver cells. For the first time, a group of researchers has unveiled a key mechanism behind the ineffective immune response and has demonstrated, using an animal model of the disease, the potential efficacy of a known molecule – a cytokine – to reactivate it. The discovery, reported today in Nature, was led by Matteo Iannacone, head of the Dynamics of the immune responses Unit at IRCCS Ospedale San Raffaele, in collaboration with Luca Guidotti, deputy scientific director of the Institute and full professor at Università Vita-Salute San Raffaele, together with Renato Ostuni, group leader of the Genomic of the innate immune system Unit. The results, obtained using sophisticated in vivo imaging technologies, pave the way for the development of new potential therapies for chronic hepatitis B.

 

 

The challenge of Chronic Hepatitis B

Hepatitis B virus (HBV) is most commonly spread through exposure to infected blood, via sexual contact or from mother to child at birth. The last form of transmission is the most common in countries – like Africa and China – where the vaccine against HBV (very effective to protect the child, if given promptly) is not always available.

HBV infection can give rise to both the acute form of the disease, which is usually resolved within a few days, and to the chronic one, for which there is no lasting cure available, but only antiviral therapies able to slow down the virus replication inside the liver. The likelihood that hepatitis B will develop from an acute infection into a chronic one depends on the age of the person infected. About 95% of adults recover completely and do not become chronically infected, while 90% of infected infants will develop chronic infection. Researchers are still trying to figure out why the immune system fails, in such cases, to eradicate the virus and how to help its activity.

 

 

New results

To answer these questions, researchers at San Raffaele are studying the subtype of T lymphocytes that gets activated by the HBV virus (called CD8+ T). Thanks to an in vivo imaging technique called intravital microscopy – developed by Matteo Iannacone – the researchers successfully demonstrate that these lymphocytes, in the case of chronic hepatitis, are dysfunctional right from the moment of their activation, which occurs by direct contact with infected cells in the liver. Moreover, through the analysis of the lymphocytes gene expression, they trace a detailed molecular portrait of these cells, which provides a great deal of information.

 

"We now know that the poor ability of the lymphocytes to react to the hepatitis B virus is different from what we see in other types of infections or cancer, when the immune response is also suppressed but through a different mechanism” explains Matteo Iannacone. Which means that drugs already used in these contexts to reactivate the immune system – such as the immune checkpoint inhibitors – may not work well in chronic hepatitis B.

 

The characterization of dysfunctional T lymphocytes has also allowed scientists to identify more suitable and effective molecules to awaken these cells. One of these has already been successfully tested in vitro: Interleukin-2, a messenger-molecule of the immune system. But the researchers hope it is only the first of a long list of candidates. "The greatest satisfaction is having developed a new technological platform, which will allow us to identify and validate new potential molecules capable of reactivating the immune system against the virus, to be tested in combination with the latest generation of antivirals," conclude Luca Guidotti and Matteo Iannacone.

 

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Alexandre P. Bénéchet, Giorgia De Simone, Pietro Di Lucia, Francesco Cilenti, Giulia Barbiera, Nina Le Bert, Valeria Fumagalli, Eleonora Lusito, Federica Moalli, Valentina Bianchessi, Francesco Andreata, Paola Zordan, Elisa Bono, Leonardo Giustini, Weldy V. Bonilla, Camille Bleriot, Kamini Kunasegaran, Gloria Gonzalez-Aseguinolaza, Daniel D. Pinschewer, Patrick T.F. Kennedy, Luigi Naldini, Mirela Kuka, Florent Ginhoux, Alessio Cantore, Antonio Bertoletti, Renato Ostuni, Luca G. Guidotti, Matteo Iannacone, Dynamics and genomic landscape of CD8⁺ T cells undergoing hepatic priming, Nature, October 2019