Treating periodontal disease through the recruitment and expansion of endogenous regulatory T cells

Periodontal disease, also known as gum disease, affects an estimated 64 million Americans and\ud is the leading cause of tooth loss. Current clinical therapies focus on the removal of invasive oral\ud bacteria that initiate the disease through scaling and root planing and administration of\ud antibiotics. However, it is now understood that tissue destruction in periodontal disease is carried\ud out by an exacerbated inflammatory immune response. Furthermore, recent literature suggests\ud that the severe forms of the disease may be characterized by a decrease in the presence of a\ud subset of cells responsible for directing immune regulation, Regulatory T cells (Tregs). To\ud address the underlying immune dysfunction, we have developed acellular approaches, utilizing\ud translatable bioerodible microspheres composed of poly(lactide-co-glycolide) capable releasing\ud factors that can recruit endogenous Tregs and induce local Tregs in the periodontium for the\ud treatment of periodontal disease. Specifically, we have developed microspheres that release the\ud Treg-associated C-C motif chemokine 22 (CCL22) and vasoactive intestinal peptide (VIP) for\ud the local recruitment of endogenous Tregs in vivo and prevention of alveolar bone resorption.\ud Furthermore, CCL22 microspheres led to a reduction in the expression of damaging\ud inflammatory mediators and conversely, led to an upregulation of anti-inflammatory molecules\ud that could potentially lead to tissue regeneration. Secondly, we demonstrate that CCL22\ud microspheres are capable of being administered using standard clinical techniques to effectively\ud treat ligature-induced periodontitis in beagle dogs. CCL22 microspheres reduce clinical scores\ud of inflammation including periodontal probing depths and bleeding on probing as well as\ud reduced tooth supporting alveolar bone resorption in dogs. Finally, we describe an alternative\ud strategy to bolster Treg population in situ, through the local expansion of Tregs by PLGA\ud microspheres releasing a combination of transforming growth factor beta (TGF-β), rapamycin\ud (Rapa) and interleukin 2 (IL-2). Administration of TGF-β, Rapa, IL-2 microspheres in a mouse model for periodontal disease significantly reduced the primary outcome of periodontal disease,\ud alveolar bone resorption. Taken together, controlled release formulations that harness the body’s\ud sophisticated immunoregulatory cells provide an easy-to-use, off-the-shelf therapeutic modality\ud for treating inflammatory periodontal disease and may become the next clinical standard\ud treatment