Inducible T cell Co-Stimulator (ICOS)-Fc Effects in Periodontitis and Periodontal Healing - 7. PROJECT SUMMARY / ABSTRACT Periodontitis is a chronic inflammatory condition characterized by the destruction of the periodontium. The leading cause of tooth loss in adults is periodontitis, which is driven by a dysbiotic microbial biofilm that colonizes the gingival sulcus. We aim to identify and characterize the role played by cells involved in the local inflammatory response to the periodontitis-associated microbial biofilm. This inflammatory response involves a network of non- immune and immune cells including keratinocytes, endothelial cells, professional antigen-presenting cells, T & B cells, and neutrophils. These cells produce cytokines and chemokines to recruit neutrophils, promote vascular proliferation, and generate osteoclasts that resorb alveolar bone. MHC antigen presentation and costimulatory signals provided by the Inducible Costimulator receptor (ICOS) and its ligand ICOSL on antigen-presenting cells play critical roles in local activation of effector/memory T cells, such as Treg, Th17 and γδ T cells. The influence of costimulatory molecules ICOS and ICOSL on the inflammatory process and bone loss in periodontitis remains unknown. In this application, we will utilize a soluble form of ICOS known as ICOS-Fc to stimulate ICOSL- expressing endothelial cells, macrophages, and osteoclasts to reduce inflammation and alveolar bone loss while also preventing the interaction of ICOSL with all cells that express ICOS, specifically Th17, Treg and γδ T cells. We hypothesize that in periodontitis, ICOS-Fc (i) prevents ICOSL from engaging ICOS+ T cells, (ii) activates ICOSL signaling, (iii) promotes M2 macrophages, and (iv) reduces alveolar osteoclastogenesis and bone loss. To test this hypothesis, we will study inflammation in a murine model of ligature-induced periodontitis by characterizing the effects of ICOS-Fc on: 1) the mucosal expansion of Th17, γδ T cells and the Treg/Th17 ratio, 2) macrophage phenotype, extravasation of neutrophils, and endothelial cell numbers, and 3) angiogenesis, macrophage distribution, and alveolar osteoclast activation resulting in alveolar bone loss. Human periodontitis has been modeled in several animal species, with each model dissecting separate aspects of the pathophysiology of this complex and fascinating disease. Available data suggest that engaging ICOSL on antigen-presenting cells with ICOS-Fc prevents the reactivation of proinflammatory Th17 cells, enhances the presence of TGFβ-expressing ICOSneg Treg cells, and reduces neutrophil infiltration. We have the tools and expertise to elucidate how engaging ICOSL affects the recruitment of innate immune cells, the expansion and contraction of Th17 and Treg cells, and osteoclast activation in vivo using our periodontitis model. We will characterize how ICOS/ICOSL signaling in Th17, γδ T cells, and Treg cells shapes the inflammatory cell environment in the gingiva, driving either the protection of the periodontium or the destruction of alveolar bone in periodontitis. Depending on whether periodontitis is mitigated or exacerbated, the results obtained here will be utilized to design therapeutic interventions aimed at modulating the ICOS-ICOSL interaction. We will identify critical targets for therapeutic interventions to reduce the economic and personal burden of periodontitis.
