BioWorld International Correspondent
LONDON - A new understanding of how the gut pathogen Helicobacter pylori manages to defeat the immune system in the stomach could allow the development of new, more specific immunosuppressive drugs with fewer side effects.
Researchers in Germany have shown that H. pylori produces a toxin that interferes with T-cell activation in a way that is very similar to the immunosuppressive drugs cyclosporin A and FK506.
Rainer Haas, professor of microbiology at the Max von Pettenkofer-Institute of the Ludwig-Maximilians University in Munich, told BioWorld International: "People had tested this toxin, which is called VacA, on epithelial cells before, but never on immune cells. This is the first evidence that VacA affects the immune system, and it explains for the first time how H. pylori is able to set up a chronic infection in the gut."
The work is reported in the Aug. 22, 2003, issue of Science in a paper titled "Helicobacter pylori Vacuolating Cytotoxin Inhibits T Lymphocyte Activation."
It is well known that H. pylori plays a role in the development of stomach ulcers. Ulcers can be healed with treatment, but they will recur if the H. pylori infection is allowed to persist. It normally is possible to eradicate it only if the patient also is prescribed antibiotics.
The evidence for a role for H. pylori in gastric cancer is less strong, but epidemiological studies have shown that people who carry the bacterium in their stomachs have a risk of developing gastric cancer that is between two and six times higher than that of people who are not infected.
Haas and his colleagues decided to investigate why the body's immune response against the bacterium is not effective. They focused on two proteins known to be secreted by H. pylori.
The first was vacuolating cytotoxin, also known as VacA, which causes vacuoles to form in epithelial cells, and eventually kills them. The second was CagA, which H. pylori directly injects into host epithelial cells.
The German team's first experiment was to add H. pylori to T cells, which play a key role in orchestrating the immune response. Normally, when T cells become activated, they secrete interleukin-2 - a growth factor for T cells - and they begin to proliferate.
"We found out very quickly," Haas said, "that H. pylori is able to completely block T-cell proliferation."
When they compared the abilities of H. pylori strains that either had the gene for VacA or the gene for CagA knocked out, they found that the mutant lacking VacA was no longer able to block T-cell proliferation, suggesting that VacA played a key role.
Because of the importance of interleukin-2 secretion in T-cell activation, their next step was to examine how VacA affected that.
"We found that the bacteria producing VacA were able to strongly inhibit the ability to produce interleukin-2," Haas said. Further experiments showed that the gene for IL-2 was blocked at the transcriptional level.
Out of the three transcription factors known to be required for transcription of the gene encoding IL-2, Haas and his colleagues found that only one - called NFAT - could be blocked by VacA.
"We discovered that NFAT, which normally goes into the nucleus of the T cell to bind to the gene for interleukin-2, does not do this when we add the VacA protein," Haas added.
To determine whether any other genes were blocked by VacA, the group used a DNA microarray to see which genes were downregulated or activated in T cells after adding VacA. They discovered that VacA modulated gene activity in a very similar fashion to immunosuppressive drugs such as cyclosporin and FK506. "We can conclude," Haas said, "that VacA uses a similar mechanism of immunosuppression as that described for cyclosporin and FK506."
The work has few direct implications for treatment of H. pylori, which can readily be eradicated by antibiotic treatment. Vaccines against H. pylori infection also are being developed. However, Haas predicts that the finding may hold the key to the development of a new generation of more specific immunosuppressive drugs with fewer side effects.
"Drugs like cyclosporin A and FK506 cannot be targeted specifically at particular types of cells. But a protein like VacA could, if coupled to antibodies, be directed solely at T cells or even certain subsets of T cells. We would like to collaborate with companies interested in pursuing this line," Haas said.
The group's next experiments will involve studying the impact of H. pylori on T cells in the guts of relevant animal models. They also plan to examine whether T cells are downregulated in biopsy samples from humans with H. pylori infection and stomach ulcers.