Vector human liver in digestive system

NMN treatment significantly increases the expression of antiviral cytokines

Hepatitis B is a viral infection that tends to be more prevalent in sub-Saharan Africa and East Asia, but it has also made its presence known in India, affecting a terribly significant number of around 40 million individuals, roughly 3% to 4.2% of the population. India falls within the range of countries with moderate hepatitis B cases globally, with a prevalence rate of 2% to 4%. Given India's large population, this poses a significant health concern, adding to the global burden of the disease. Disturbingly, 15% to 25% of people with chronic hepatitis B in India face serious complications such as liver cirrhosis, liver cancer, and an increased risk of premature mortality.

While most cases of hepatitis B resolve within six months, some persist and become chronic troublemakers. This occurs when CD8 T cells, the heroic virus-fighting immune cells, become exhausted from their relentless battle. Their exhaustion leads to DNA damage and weakens their ability to combat the virus. Understanding the reasons behind CD8 T cell exhaustion is crucial for developing improved treatments for chronic hepatitis B. Some researchers suggest that NAD+, a substance naturally present in the body, may play a role in this exhaustion process.

Excitingly, a recent study by Fisicaro et al. from the University of Parma in Italy, published in the Journal of Hepatology, introduces a potential treatment approach for chronic hepatitis B. The researchers discovered that by targeting specific CD8 T cells that combat the hepatitis B virus with a substance called nicotinamide mononucleotide (NMN), they could give these cells a much-needed power boost. Exhausted hepatitis B-specific CD8 T cells were found to have higher levels of DNA damage and impaired DNA repair mechanisms. However, NMN or inhibitors of the CD38 enzyme have the potential to rejuvenate these exhausted T cells, enabling them to mount a formidable defense against hepatitis B and even other virulent infections.

(Montali et al., 2023 | Journal of Hepatology) NMN restores immune cell antiviral cytokine production. Cellular cytokines listed on the X-axis significantly increased following immune cell treatment with NMN and hepatitis B viral proteins (black bars) compared to those treated with hepatitis B viral proteins alone (gray bars). Med + Pep= Cell culture medium with viral peptide stimulation; Med + Pep + NMN= Cell culture medium with viral peptide stimulation and NMN

Furthermore, the study revealed that replenishing NAD+ levels in CD8 T cells isolated from chronic hepatitis B patients through NMN treatment significantly increased the expression of antiviral cytokines, particularly interferon-gamma (IFN-γ), which experienced a remarkable 2.7-fold increase. This suggests that NMN holds promise in restoring the antiviral properties of CD8 T cells.

(Montali et al., 2023 | Journal of Hepatology) Hepatitis B-specific CD8 T cells have high levels of DNA damage and a weak DNA damage response to a DNA damaging molecule (etoposide). Left) Compared to FLU-specific CD8 T cells (FLU HEALTHY), those specific for hepatitis B (HBV CHRONIC) exhibit higher levels of markers for DNA damage (phosphoH2AX). Right) A molecule used to induce DNA damage (etoposide) elicits a trend toward lower DNA damage response in hepatitis B-specific immune cells (HBV CHRONIC) compared to FLU-specific immune cells (FLU HEALTHY), suggesting lower NAD+ required for DNA repair.

In an intriguing comparison between hepatitis B-specific T cells and influenza-specific T cells, the study observed much higher levels of DNA damage in the former group. Additionally, when exposed to a substance inducing DNA damage, hepatitis B-specific T cells exhibited a weaker response compared to influenza-specific T cells. These findings indicate that the diminished NAD+ levels are associated with increased DNA damage in exhausted hepatitis B-specific CD8 T cells, as DNA damage responses heavily rely on NAD+ availability.

(Montali et al., 2023 | Journal of Hepatology) Higher immune cell CD38 enzyme levels are associated with lower antiviral cytokine levels. Higher percentages of immune cells with elevated CD38 (%CD38hi) are associated with a lower probability of expressing the antiviral cytokine IFN-𝛾 (%IFN-𝛾+).

Our data show increased DNA damage with limited activation of the DNA repair machinery in [hepatitis B virus]-specific CD8 T cells from [chronic hepatitis B] patients,” say Fisicaro and colleagues. This strongly suggests that NAD-consuming enzymes, particularly overexpressed CD38, may play a pivotal role in NAD depletion. Reconstitution of many interconnected intracellular functions by NMN supplementation indicates that NAD depletion likely represents an important determinant of T cell exhaustion.”

Higher CD38 enzyme levels can impede the production of antiviral cytokines.

Moreover, the study found a correlation between elevated levels of the NAD+-consuming enzyme CD38 and reduced levels of IFN-γ, a vital cytokine involved in antiviral defense. This suggests that higher CD38 enzyme levels can impede the production of antiviral cytokines, supporting the hypothesis that low NAD+ levels contribute to the development of chronic hepatitis B, as increased CD38 levels theoretically deplete cellular NAD+.

To sum it up, this study provides compelling evidence that the hepatitis B virus triggers the activation of the CD38 enzyme, resulting in a shortage of NAD+. Consequently, exhausted hepatitis B-specific T cells suffer from increased DNA damage, accompanied by compromised DNA repair mechanisms.

NMN could play a vital role in empowering immune cells

However, there is a silver lining. Treating CD8 T cells with NMN, a precursor to NAD+, has yielded promising results in reviving the production of antiviral cytokines. This suggests that replenishing NAD+ levels rejuvenates the functionality of these T cells. These findings lend support to the idea that NAD+ depletion contributes to the exhaustion and dysfunction of CD8 T cells. Further research is needed to determine if NMN can restore exhausted T cells in the context of other infections. Should NMN prove effective in treating various infections, it could indicate that NAD+ plays a vital role in empowering immune cells to combat a wide range of infectious diseases.

Thinking of trying NMN to boost your immunity? Read Top 5 NMN Supplements In India: A Brief Review