PROJECT SUMMARY Periodontal disease (PD) is chronic inflammatory disorder characterized by the infection of gingiva, connective tissue and alveolar bone. Dense immune cell infiltrates are characteristic in PD, of which T cells are key mediators of the host response and are significant participants in PD progression. Among the participating T cell subsets, regulatory T cells (Treg) have been identified in PD-affected tissue and generally function to suppress pro-inflammatory T cells. However, in chronic inflammatory lesions, Treg may lose immunoregulatory function and, instead, produce pro-inflammatory cytokines. We hypothesize that restoring Treg function will influence the immune response in PD. To test the hypothesis, the project will develop immunomodulatory microparticles to functionally stabilize Treg in periodontal tissue. The project comprises two aims – Aim 1 will optimize the synthesis of biodegradable microparticles for encapsulating immunomodulatory factors. We will measure and tune the rate of release to sustain biologically relevant concentrations for mediating immunomodulation. By measuring in vitro immunophenotypic stability and cytokine production by Treg, we will assess bioactivity of the released factors. Aim 2 will test microparticle delivery in a mouse periodontitis model. We will measure in vivo degradation and quantify the local enhancement of Treg mediated by the microparticles. We will conduct functional measurements by measuring the concentrations of associated cytokines and tissue inflammation using histomorphometry-based analysis. Overall, the experiments will evaluate the feasibility of in vivo Treg expansion and stabilization for attenuating inflammation in PD. The PI is a New Investigator with expertise in drug delivery, tissue engineering and immunology and will collaborate with the co-I, a clinician-scientist with expertise in autoimmune disease with a focus on how inflammation-induced Treg instability results in pathogenic production of inflammatory cytokines. The results from the project will assess the feasibility of microparticle-mediated modulation of inflammatory T cells in PD and lead to a R01 grant application to comprehensively characterize immunomodulation for durably controlling chronic inflammation in PD.