Collaborating Investigator: Steven Little
Affiliation: University of Pittsburgh

Funding Source: NIH
Grant Number: U24DE026915
Project Period: 03/01/17-02/29/20
Project Status: New

Significance

Periodontal disease affects over 78 million Americans and is considered the most pressing oral health concern today. Also known as periodontitis, this condition is characterized by destructive inflammation of the periodontium, including the gum tissue, supporting bone, and ligament. Importantly, this disease affects not only tooth loss, but also the incidence of cardiovascular disease, kidney disease, respiratory diseases, diabetes, and even premature childbirth. The current standard of care involves debridement of calculus and can be accompanied by local delivery of an antibiotic such as minocycline. These treatments temporarily kill pathogens, but neither protect against inevitable future infections nor address the sensitivity observed in patients disposed to immune dysfunction. Although invasive bacterial species are protagonists of the disease, tissue destruction is mediated by an adverse host inflammatory immune response. As the disease progresses, several populations of lymphocytes are recruited to the periodontium. A newlydiscovered subset of lymphocytes called regulatory T cells (Tregs) has been shown to play a critical role in the regulation of harmful aberrant inflammatory immune responses. Recently, we have demonstrated that the presence/absence of Tregs correlates with the presence/absence of advanced periodontal disease. In the absence of Tregs, inflammatory cytokines are produced, ultimately leading to bone resorption. Conversely, the presence of regulatory lymphocytes leads to an environment conducive to immunological homeostasis and healing.

Approach

Aim 1: To engineer improved formulations that produce long-lasting release of Treg-inducing factors for the treatment of periodontitis.
Aim 2: To understand the role of recruited Treg in inflammation and disease abrogation

This project is based on an innovative hypothesis that controlled delivery of Treg chemoattractants in the periodontium can promote localization of endogenous Tregs and abrogate periodontal disease symptoms. By recruiting endogenous Tregs to the periodontium, we intend to leverage the body’s inherent and sophisticated mechanisms for immune regulation. Our hypothesis is supported by preliminary data demonstrating that: 1) controlled release of CCL22 leads to the recruitment of endogenous, FoxP3+ Tregs to the periodontium, 2) administration of CCL22 controlled-release formulations leads to both higher numbers of Tregs in draining lymph nodes and resolution of periodontal disease symptoms in two different models of murine periodontitis.

CP: Controlled release of CCL22 will be combined with TolAPC nanoimmunomaterials developed as part of TR&D2 to both attract Tregs and drive their expansion to treat periodontitis.

Push-Pull relationship:

The goal of this funded project in the Little lab is to develop a non-antibiotic, controlled release system that mimics the body’s natural immune regulation mechanisms and harnesses natural, endogenous cells as agents of periodontal disease treatment. This design of controlled release of biomolecules for immunomodulation of Tregs (pull) is synergistic with the immunosuppressive tolerogenic antigen–presenting particles (TolAPC) that are being developed in TR&D 2 that induce tolerance through presentation of biomolecules from a biomimetic surface (push). Nanoimmunomaterials (NIM) for immune tolerance developed as part of TR&D 2 will be modified further (push) by tuning the biomolecules conjugated to their surfaces and by optimizing the biomolecules encapsulated within them for sustained release based on the results and needs of the Little lab (pull). Further, controlled release systems developed by the Little lab will be evaluated in combination with tolerogenic particles from TR&D 2 in order to lead to Treg expansion (pull). Nanoimmunomaterials from TR&D 2 will thus push and be pulled by the science of the CP and in addition, these interactions will broaden the applications and utility of the fundamental NIM technology for treating autoimmune diseases.