Research Suggests New Strategy to Prevent Gum DiseaseBy Abigail Pfeiffer on December 11, 2012 | 0 comments
According to a University of Pennsylvania press release, by blocking a molecular receptor that bacteria normally target to cause the disease, scientists from the university have now demonstrated an ability in a mouse model to both prevent periodontitis from developing and halt the progression of the disease once it has already developed.
The study, published in the Journal of Immunology, was led by Toshiharu Abe, a postdoctoral researcher in the Department of Microbiology at the Penn School of Dental Medicine. Abe works in the lab of George Hajishengallis, a professor in the department who was a senior author on the paper. The co-senior author wasJohn D. Lambris, the Dr. Ralph and Sallie Weaver Professor of Research Medicine in the Department of Pathology and Laboratory Medicine in Penn's Perelman School of Medicine.
In previous research, Hajishengallis, Lambris and colleagues showed that Porphyromonas gingivalis, the bacterium responsible for many cases of periodontitis, acts to “hijack” a receptor on white blood cells called C5aR.
The release notes that by hijacking C5aR, P. gingivalis subverts the complement system and handicaps immune cells, rendering them less able to clear infection from the gum tissue. As a result, numbers of P. gingivalis and other microbes rise and create severe inflammation. According to a study published last year, “Low-Abundance Biofilm Species Orchestrates Inflammatory Periodontal Disease through the Commensal Microbiota and Complement” by the Penn researchers, mice bred to lack C5aR did not develop periodontitis.
In the new study, the Penn team wanted to determine if the synergism seen by other scientists between the complement system and TLRs was also at play in this inflammatory gum disease.
To find out, they injected two types of molecules, one that activated C5aR and another that activated TLR2, into the gums of mice. When only one type of molecule was administered, a moderate inflammatory response was apparent a day later, but when both were injected together, inflammatory molecules increased dramatically — soaring to levels higher than would have been expected if the effect of activating both receptors was merely additive.
This finding suggested to the scientists that the Toll-like receptor signaling was somehow involved in "crosstalk" with the complement system, serving to augment the inflammatory response. Turning that implication on its head, they wondered whether blocking just one of these receptors could effectively halt the inflammation that allows P. gingivalis and other bacteria to thrive and cause disease.
Testing this hypothesis, the researchers synthesized and administered a molecule that blocks the activity of C5aR, to see if it could prevent periodontitis from developing. They gave this receptor "antagonist," known as C5aRA, to mice that were then infected with P. gingivalis. The C5aRA injections were able to stave off inflammation to a large extent, reducing inflammatory molecules by 80 percent compared to a control, and completely stopping bone loss.
And when the mice were given the antagonist two weeks after being infected with P. gingivalis, the treatment was still effective, reducing signs of inflammation by 70 percent and inhibiting nearly 70 percent of periodontal bone loss.
“Regardless of whether we administered the C5a receptor antagonist before the development of the disease or after it was already in progress, our results showed that we could inhibit the disease either in a preventive or a therapeutic mode,” Hajishengallis said. This is significant for extending these findings to a potential human treatment, as treatments would most likely be offered to those patients already suffering from gum disease.
The team is now working to replicate their success in mice in other animal models, an important step toward extending this kind of treatment to humans with gum disease. The study was supported by the National Institutes of Health.