JIJITANG2014-08-21 4:38 PM

TARGET IMMUNE SYSTEM TO TREAT GUM DISEASE

A component of the immune system may offer a new target for preventing or even reversing gum disease, researchers say.

Nearly half of all adults in the United States suffer from periodontitis—and 8.5 percent have a form that is serious enough that it can raise the risk of heart disease, diabetes, arthritis, and pregnancy complications.

For a new study with monkeys, an inhibitor that blocks the component, called complement, successfully prevented the inflammation and bone loss that are associated with periodontitis, making it a promising drug for treating humans with the disease.

Earlier work by researchers showed that the periodontal 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 a professor of microbiology in the dental medicine department at University of Pennsylanvia. “So P. gingivalis helps suppress the immune system in a way that creates a hospitable environment for the other bacteria.”

For the new study, published in the Journal of Immunology, Hajishengallis and colleagues wanted to find out which component of the complement system might be involved in contributing to and maintaining inflammation in the disease. Their experiments 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.

BALANCE OF BACTERIA
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. C3-deficient mice were also protected from periodontitis in two additional models of disease: one in which a silk thread is tied around a tooth, promoting the build-up of microbes, and one in which the disease occurs naturally in aging mice, mimicking how the disease crops up in aging humans.

“Without the involvement of a different complement component, the C5a receptor, P. gingivalis can’t colonize the gums,” Hajishengallis says. “But without C3, the disease can’t be sustained over the long term.”

Building on this finding, 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. They found that the C3 inhibitor, a drug called Cp40 that was developed for the treatment of the rare blood disease PNH and ABO-incompatible kidney transplantation, reduced inflammation and significantly protected the monkeys from bone loss.

“We think this drug offers a promising possibility for treating adults with periodontitis,” says coauthor John Lambris, professor of research medicine. “Blocking C3 locally in the mouth helps shift the balance of bacteria, producing an overall beneficial effect.”

The study represents the first time, to the researchers’ knowledge, 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 results, “provide proof-of-concept that complement-targeted therapies can interfere with disease-promoting mechanisms,” Hajishengallis says.

The National Institutes of Health, the European Commission, and the University of Pennsylvania Institute for Translational Medicine and Therapeutics supported the research.

Original Article: 
《Genetic and Intervention Studies Implicating Complement C3 as a Major Target for the Treatment of Periodontitis》, Published on Journal 《The Journal of Immunology》in April 11, 2014. 

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