Researchers at the University of Pennsylvania have discovered a new target for preventing halving and reversing periodontitis. Referred to as Complement this component of the innate immune system can interfere with disease-promoting mechanisms by blocking and preventing disease.
In a report, published in the Journal of Immunology, the researchers state that treating monkeys with a complement inhibitor successfully prevented the inflammation and bone loss that is associated with periodontitis, which makes this a promising drug for treating humans with the disease. The study represents the first time that anyone has demonstrated the involvement of Complement in inflammatory bone loss in non-human primates, setting the stage for translation to human treatments.
The researchers had previously demonstrated that the bacterium Porphyromonas gingivalis can hamper the ability of immune cells to clear infection, allowing P gingivalis and other bacteria to flourish and inflame the gum tissue. P gingivalis has many mechanisms to escape killing by the immune system, but getting rid of inflammation altogether is not good for them because they feed off of it, says George Hajishengallis, senior author of the report and professor in the school of Dental Medicines Department of Microbiology. So P gingivalis helps suppress the immune system in a way that creates a hospitable environment for the other bacteria.
The C3 Receptor
With a goal of finding out which component of the Complement system might be involved in contributing to and maintaining inflammation in the disease, the researchers focused on the third component of Complement C3 which occupies a central position in signaling cascades that trigger inflammation and activation of the innate immune system. They discovered that mice bred to lack C3 had much less bone loss and inflammation in their gums several weeks after being infected with P gingivalis compared to normal mice. The C3-deficient mice were also protected from periodontitis in two additional models of disease. One involving a silk thread tied around a tooth promoting the build-up of microbes, and the other where the disease occurred naturally in aging mice to mimic how the disease crops up in aging humans.
Next, the researchers tested a human drug that blocks C3 to see if they could reduce the signs of periodontal disease in monkeys, which unlike mice, are responsive to the human drug. This revealed that the C3 inhibitor called Cp40 and developed for the treatment of rare blood diseases PNH and ABO-incompatible kidney transplantation reduced inflammation and significantly protected the monkeys from bone loss.
Without the involvement of a different complement component - the C5a receptor P gingivalis cant colonize the gums, Hajishengallis said. But without C 3, the disease cant be sustained over the long term. The results provide proof-of-concept that complement-targeted therapies can interfere with disease-promoting mechanisms.
We think the drug offers a promising possibility for treating adults with periodontitis, added co-senior author John Lambris. Blocking C3 locally in the mouth helps shift the balance of bacteria, producing an overall beneficial effect.