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Infection with hepatitis D viruses causes severe inflammation of the liver. An MHH team has now identified a marker on natural killer cells that is influenced by the anti-inflammatory effectiveness of the drug bulevirtide.
Hepatitis D viruses (HDV) cause the most severe form of chronic, virus-related hepatitis. The active ingredient bulevirtide has been on the European market since mid-2023 as the only approved treatment option to date. The drug attaches to the binding site that blocks the docking point for the viral envelopes on the liver cell. As this is now occupied, the HD viruses can no longer enter the cell. At the same time, bulevirtide alleviates the liver inflammation early on during treatment, when the viral load is still relatively high. Researchers at the Department of Gastroenterology, Hepatology, Infectiology and Endocrinology at Hannover Medical School (MHH) have now investigated how bulevirtide influences the immune system. The team led by Dr Norman Woller and Clinic Director Professor Dr Heiner Wedemeyer has discovered that natural killer cells (NK cells) play an important role in this process. The results have been published in the scientific journal ‘Hepatology’.
Double infection causes ‘fire in the liver’
HDV is a so-called incomplete virus and needs the hepatitis B virus (HBV) as a helper in order to package its RNA genetic material in its envelope, dock onto the liver cell and penetrate it. A hepatitis D infection therefore only occurs as a co-infection with a hepatitis B infection. ‘Hepatitis D exacerbates the existing HBV infection and causes a fire in the liver, so to speak,’ says Dr Woller. Hepatitis D is a rare disease that affects around ten to 20 million people worldwide. However, the virus is considered to be particularly aggressive and can quickly lead to liver cirrhosis or liver cancer, which is why it is also referred to in medicine as the ‘devil variant’.
The research team analysed the immune system of patients suffering from chronic hepatitis D (CHD) who were treated with bulevirtide. ‘The cohort of 20 hepatitis D cases consisted exclusively of patients from the MHH,’ emphasises Professor Wedemeyer, who led the clinical development of the drug.‘ For such a rare disease, this is an unusually high number of cases for a single clinic and is due to the fact that we have been collecting blood samples before, during and after treatment for a long time with the consent of those affected and using them for research purposes.’
Altered marker on immune cells
The researchers focussed on the innate immune system, in particular the natural killer cells (NK). These immune cells are our first line of defence, so to speak, and are primarily directed against cells infected by viruses and against cancer. We suspected that BLV treatment could influence the immune cells in CHD patients and carried out a high-resolution analysis of NK cells before and during BLV therapy,’ says Dr Norman Woller. While the number of NK cells themselves remained stable overall during BLV treatment, the researchers were able to detect significant changes in a marker called TIGIT on the surface of the NK cells, which is important for the immune response, in a specific CHD group before and during the therapy.
TIGIT is one of the so-called immune checkpoint proteins that offer promising approaches for cancer therapy. This is because cancer cells, together with cells from the immediate tumour environment, can suppress the immune response. The TIGIT signalling pathway plays an important role in this. The immune receptor TIGIT is found on various types of immune cells and acts as a brake, so to speak, to prevent excessive inflammatory reactions. ‘If TIGIT is missing or the checkpoint is switched off, the actually desired inflammatory reaction of the immune system gets out of hand, so to speak,’ explains Po-Chun Chen, research associate at the clinic and first author of the study.
Bulevirtide switches NK cell brake on again
In the course of treatment with bulevirtide, the activation of TIGIT increased significantly. At the same time, the levels of the enzyme alanine aminotransferase, a marker for liver inflammation, fell. This was not the case in the control groups of patients with chronic hepatitis C and chronic hepatitis B. ‘The lack of TIGIT activity on certain NK cells is apparently a sign of liver inflammation in an HDV infection,’ surmises Dr Woller. Treatment with bulevirtide may switch the brakes on the inflammatory reactions again and could therefore be the trigger as to why the liver inflammation recedes and the liver enzymes improve rapidly during therapy. ‘Clarifying the influence of bulevirtide on the TIGIT signalling pathway could help to develop new drugs against liver inflammation,’ hopes the biochemist.
SERVICE:
A summary of the original paper ‘TIGIT-expression on natural killer cell subsets is an early indicator of alleviating liver inflammation following bulevirtide treatment in chronic hepatitis D’ can be found here: https://journals.lww.com/hep/abstract/9900/tigit_expression_on_natural_killer_ce...
A summary of the pivotal trial for the drug bulevirtide ‘A Phase 3, Randomised Trial of Bulevirtide in Chronic Hepatitis D’ can be found here: https://www.nejm.org/doi/full/10.1056/NEJMoa2213429#summary-abstract
For further information, please contact Dr Norman Woller, woller.norman@mh-hannover.de.
Have found out how the drug Bulevirtide alleviates liver inflammation in hepatitis D infections: (fr ...
Copyright: Karin Kaiser/MHH
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Have found out how the drug Bulevirtide alleviates liver inflammation in hepatitis D infections: (fr ...
Copyright: Karin Kaiser/MHH
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