December 7, 2012
PHILADELPHIA — Periodontitis, a form of chronic gum disease that affects nearly half of
adult population, results when the bacterial community in the mouth becomes
unbalanced, leading to inflammation and eventually bone loss. In its most
severe form, which affects 8.5 percent of U.S. adults, periodontitis can
impact systemic health.
By blocking a molecular
receptor that bacteria normally target to cause the disease, scientists from
the University of Pennsylvania 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
The study, published in
the Journal of
Immunology, was led by Toshiharu Abe, a postdoctoral researcher in the Department
of Microbiology in Penn’s 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 was John 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. Kavita B. Hosur and Evlambia
Hajishengallis from Penn Dental Medicine also contributed to the research,
as did Penn Medicine’s Edimara S. Reis
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 receptor is part of the
complement system, a component of the immune system that helps clear infection
but can trigger damaging inflammation if improperly controlled.
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 by the Penn researchers, mice bred to lack C5aR did not
Meanwhile, other studies
by the Penn group and others have shown that Toll-like receptors, or TLRs — a
set of proteins that also activate immune cell responses — may act in concert
with the complement system. In addition, mice lacking one form of TLR called
TLR2 do not develop bone loss associated with periodontitis, just like the
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
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.
Because not all cases of
periodontitis are caused by P. gingivalis, the research team also wanted to see
whether C5aRA could effectively prevent or treat the disease when it arose due
to other factors. To do so, they placed a silk ligature around a single molar
tooth in a group of mice. The obstruction not only blocked the natural cleaning
action of saliva, but also enabled bacteria to stick to the ligature itself,
resulting in a massive accumulation of bacteria. This microbial build-up
rapidly leads to periodontitis and bone loss, within just five days in the
The researchers then
injected the gum tissue adjacent to the ligated molar tooth with C5aRA in some
of the mice, and gave the other mice a control.
“These mice that got the
C5a receptor antagonist developed at least 50 percent less inflammation and
bone loss compared to an analog of C5a receptor antagonist which is not
active,” Hajishengallis said.
This result gives the
researchers greater confidence that the C5aRA treatment could be effective
against periodontitis in general, not just those cases caused by P. gingivalis
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.
“Our ultimate goal is to
bring complement therapeutics to the clinic to treat periodontal diseases,”
Lambris said. “The complement inhibitors, some of which are in clinical trials,
developed by my group are now tested in various periodontal disease animal
models and we hope soon to initiate clinical trials in human patients.”
The study was supported
by the National Institutes of Health.