Blocking of IL-6 function to prevent Pg mediated Th17 response

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DESCRIPTION (provided by applicant): Th17 cells are emerging as critical players in many chronic inflammatory diseases including chronic periodontitis. Periodontal disease, besides being the most prevalent form of bone pathology in humans, is a risk factor for life-threatening conditions such as cardiovascular diseases and diabetes. Attempts to describe the pathogenesis of periodontal disease within the conceptual framework of Th1/ Th2 model have been inconclusive. Several human studies in CP have shown elevated levels of IL-17, signature cytokine of Th17 cells, and presence of Th17 cells in the inflamed gingiva. However, underlying mechanism of Th17 differentiation and their role in the pathogenesis of CP is not known. In this regard, pro-inflammatory pleotropic cytokine IL-6 plays a critical role, in differentiation of Th17 cells, and inhibition of regulatory T cells. Due to this role of IL-6, blocking of IL-6 function ha become an attractive target for treatment of chronic inflammatory and autoimmune diseases. Many clinical trials involving blocking of IL-6 signaling molecules are currently ongoing. In line with this, CP, although is initiated by microbes, which include P. gingivalis, disease pathogenesis and progression is immune mediated with high levels of IL-6. P. gingivalis implicated in CP relies on multiple virulence factors like fimbriae, LPS and cysteine proteinases ginipains (RgpA and RgPB) which use different signaling receptors to exert their influence. While, fimbriae FimA/ Pg LPS targets TLR2, gingipains (RgpA, RgpB) signal through PAR-2. Both the receptors are expressed by human dendritic cells. In view of this information, major hypothesis of the proposal is that Pg PAMP's, adhesins and gingipains which use different PRR's have distinct immune-modulatory roles in TH17 differentiation and blocking of IL-6 signaling molecules represents an important therapeutic target to prevent Pg initiated Th17 differentiation. The major objective of this proposal is to identify molecular therapeutic targets o inhibit Pg and its PAMP's mediated Th17 differentiation and bone loss. To address this we will focus on two approaches, first we will investigate the potential of Pg and it PAMP's in induction of IL-6, regulation of IL-6 signaling molecules and in Th17 differentiation by in-vitro cultured monocyte derived dendritic cells (MoDCs).Second we will target IL-6 signaling molecules: a) IL-6 receptor (IL-6R) with anti- IL-6R antibodies, b) signal transducing protein gp130Fc and c) Jak2 inhibitor which have been proven to be effective in many chronic inflammatory and autoimmune diseases. The Long term goal of this study is to develop immune-modulatory intervention strategies for fine- tuning the host response, to maximize the protective response and minimize the destructive aspects of the periodontal host response. Positive findings will establish the regulation of human Th17 cells by P. gingivalis adhesins and gingipains. Results of the present investigation will be useful in design of novel therapeutic targets.