Hepatology: A boost in defense
Published online 16 March 2011
Gene therapy restores adaptive immunity in patients with chronic hepatitis B and directs T cells to tumor cells in patients with hepatitis B virus-related hepatocellular carcinoma
The process of TCR gene transfer inserts gene materials into T cells to restore their immunity
Hepatitis B virus (HBV) is the culprit behind hepatitis B, a type of liver infection that affects people all over the world, particularly those in China, Southeast Asia and Africa. An HBV infection might either be acute (brief) or chronic (long-lasting). Acute HBV infection may cause a variety of symptoms, including yellow skin and eyes, nausea and abdominal pain, but rarely death. Chronic HBV infection is more dangerous and can lead to severe consequences, such as cirrhosis and hepatocellular carcinoma (HCC), that are often fatal.
Patients with acute HBV infection usually do not require treatment because their body is equipped with T cells, a special type of immune cells that is capable of eliminating various virally infected and tumor cells. Unfortunately, T cells that specifically target HBV are either deleted or dysfunctional in patients with chronic HBV infection.
Current treatments, such as antiviral therapy, can reduce the number of HBVs in the body and clear the virus from the bloodstream, but are unable to eliminate HBV completely from the liver or set up immunity against HBV. As a result, patients with chronic HBV infection must pay for expensive treatments and remain at risk of HCC for the rest of their life. Antonio Bertoletti at the A*STAR Singapore Institute for Clinical Sciences and co-workers1 have now investigated the possibility of using gene therapy to restore the immune response of T cells towards HBV.
The researchers inserted HBV-specific T cell receptor (TCR) genes into T cells obtained from patients with and without chronic HBV infection (see image). They used immunostaining to demonstrate that T cells from both groups of patients expressed the same amount of TCRs on the cell surface after gene transfer. They also used intracellular staining to show that the T cells could produce interferon, tumor necrosis factor and interleukin—cytokines for inhibiting viral replication, tumor growth and microbial infection.
The researchers tested the genetically modified T cells on various cell lines and found that the T cells could destroy HBV-infected liver cells and recognize HCC cells expressing HBV antigen. They also tested the genetically modified T cells on mice and showed that the T cells were effective in reducing tumor growth.
“Our findings suggest that HBV-specific TCR gene transfer could potentially be used in HBV-HCC patients to target tumors and the underlying infection,” says Bertoletti. If true, the new gene therapy could help save millions of lives and generate important revenue.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Institute for Clinical Sciences
- Gehring, A. J. et al. Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. Journal of Hepatology Published Online: 23 Nov 2010 | DOI: 10.1016/j.jhep.2010.10.025 | article