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Drivers of inflammation provide valuable targets for new gum disease therapies

October 17, 2018

T cells help fight off infection, but they can go overboard. A new study led by researchers at the University of Pennsylvania School of Dental Medicine and the National Institutes of Health (NIH) shows that a subset of T cells contributes to the problematic inflammation and bone loss that is associated with periodontitis, a severe form of gum disease.

The research, conducted with the help of animal models and a group of human patients with a rare genetic mutation, point to a new target for treating periodontitis, as well as other diseases involving the inappropriate response of this group of T cells, known as Th17 cells. These include autoimmune conditions such as rheumatoid arthritis and multiple sclerosis. The work appears in Science Translational Medicine.

"I think this work leaves no doubt that these cells are important mediators of periodontitis," says George Hajishengallis, the Thomas W. Evans Centennial Professor in the Department of Microbiology at Penn Dental Medicine. "The translational aspect of our studies is pinpointing a new approach to blocking the tissue destruction we see in periodontitis, by inhibiting Th17 development."

Hajishengallis collaborated on the work with Niki M. Moutsopoulos of the NIH's National Institute for Dental and Craniofacial Research, with whom he has made previous insights into the molecular drivers of periodontitis.

T cells are broadly considered to fall into two categories: helper T cells, which aid in orchestrating the immune system's response to threats, and cytotoxic T cells, which take a lead role in carrying out an attack. Until about 13 years ago, helper cells were further divided into two groups: Th1 or Th2 cells. Then a new subset, Th17 cells, was identified, and researchers quickly realized Th17 cells played a role in certain human diseases. By 2008, Hajishengallis and other researchers began to suspect that these cells may be implicated in periodontitis. More recent studies have found that people with chronic periodontitis have an unusually high number of Th17 cells in their gum tissue, but these investigations hadn't uncovered the particular role of these cells in the condition or whether they were required for the development of periodontitis.

In the current work, the researchers looked at gum tissue from patients with chronic periodontitis and confirmed that they had higher numbers of Th17 cells compared to healthy controls, with the numbers correlating with the severity of disease. In parallel, they observed that mice in which periodontitis was induced, Th17 cell numbers, along with the IL-17 signaling molecule which they produce, increased with the onset of gum disease. This increase in Th17 cell numbers, the researchers found, was the result of local proliferation rather than recruitment from nearby lymph nodes.

To interrogate possible triggers of the local expansion of Th17 cells, the team decided to see how changes in the community of microbes in the gum tissue, the gingival microbiome, affected the accumulation of Th17 cells. In the mouse model of disease, animals were treated with broad- or narrow-spectrum antibiotics. Only those antibiotics which lowered the numbers of Th17 cells were capable of suppressing the disease, again implicating these cells in disease.

To definitively link the cells to the condition, however, the researchers took advantage of a mouse model missing a key protein required for Th17 cell development, as well as a population of human patients with a mutation in the corresponding gene, Stat3, who are monitored at the NIH. In both cases, they found that the Stat3 mutation, which dramatically cut the number of Th17 cells present in the gum tissue, also protected against the bone loss seen in chronic periodontitis. While people with this Stat3 mutation have other problems, gum disease is not one of them.

"Here we have a unique patient population with the same defect we checked in the mice, and they are similarly not susceptible to the same disease," Hajishengallis says. "This type of rigorous evidence is not easy to come by in medical science."

Though antibiotics could serve to protect against the disease, the side effects of taking such drugs, which can kill both beneficial and disease-causing microbes throughout the body, are too significant to recommend the treatment for broad use. But employing a small-molecule that inhibits Th17 cell development gave the researchers a similar effect, reducing Th17 cell accumulation and associated periodontal bone loss in mice.

"There is no antibiotic that is that targeted, that specific," Hajishengallis says. Such an inhibitor offers promise as a periodontal therapy and perhaps as a target for treating other diseases in which Th17 play a destructive role.
-end-
Nicolas Dutzan of NIH was first author on the study, and sharing co-second authorship were Tetsujiro Kajikawa of Penn Dental and Loreto Abusleme of NIH. Other coauthors included NIH's Tersa Greenwell-Wild, Carlos E. Zuazo, Tomoko Ikeuchi, Laurie Brenchley, Charlotte Hurabielle, Daniel Martin, Robert J. Morell, Alexandra F. Freeman, Vanja Lazarevic, Giorgio Trinchieri, Steven M. Holland, and Yasmine Belkaid; Penn Dental's Toshiharu Abe; and University of Connecticut Health's Patricia I. Diaz.

The study was supported by the National Institutes of Health (grants DE024153 and DE026152 and intramural programs), La Roche-Posay, CEDEF, the Fondation Groupe Pasteur Mutualité, the Société Française de Dermatologie, the Philippe Foundation, and the Fondation pour la Recherche Médicale.

University of Pennsylvania

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