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

描述（由申请人提供）：Th 17细胞正在成为许多慢性炎症性疾病（包括慢性牙周炎）的关键参与者。牙周病除了是人类最普遍的骨病理形式之外，还是危及生命的疾病如心血管疾病和糖尿病的危险因素。试图描述牙周病的发病机制的概念框架内的Th 1/Th 2模型一直没有定论。在CP中的几项人体研究显示IL-17水平升高，Th 17细胞的标志性细胞因子，以及发炎牙龈中Th 17细胞的存在。然而，Th 17分化的潜在机制及其在CP发病机制中的作用尚不清楚。在这方面，促炎性多效性细胞因子IL-6在Th 17的分化中起关键作用 细胞和抑制调节性T细胞。由于IL-6的这种作用，阻断IL-6功能已成为治疗慢性炎症和自身免疫性疾病的有吸引力的靶点。许多涉及阻断IL-6信号分子的临床试验目前正在进行中。与此一致，尽管CP是由微生物（包括牙龈卟啉单胞菌）引发的，但疾病的发病机制和进展是由高水平的IL-6免疫介导的。涉及CP的牙龈卟啉单胞菌依赖于多种毒力因子，如菌毛、LPS和半胱氨酸蛋白酶ginipains（RgpA和RgPB），其使用不同的信号传导受体来发挥其影响。而菌毛FimA/ Pg LPS靶向TLR 2，牙龈蛋白酶（RgpA，RgpB）通过PAR-2信号传导。这两种受体都由人树突细胞表达。鉴于这一信息，该提议的主要假设是使用不同PRR的Pg PAMP、粘附素和牙龈卟啉菌蛋白酶在Th 17分化中具有不同的免疫调节作用，并且IL-6信号传导分子的阻断代表了防止Pg引发的Th 17分化的重要治疗靶点。本研究的主要目的是确定抑制Pg及其PAMP介导的Th 17分化和骨丢失的分子治疗靶点。为了解决这个问题，我们将集中在两种方法上，首先，我们将研究Pg和它的PAMP在诱导IL-6、调节IL-6信号传导分子和体外培养的单核细胞衍生的树突状细胞（MoDC）的Th 17分化中的潜力。a）IL-6受体（IL-6 R）与抗IL-6 R抗体，B）信号转导蛋白gp 130 Fc和c）Jak 2抑制剂，其已被证明在许多慢性炎性和自身免疫性疾病中有效。本研究的长期目标是开发用于微调宿主反应的免疫调节干预策略，以最大化牙周宿主反应的保护性反应并最小化破坏性方面。阳性发现将确立牙龈卟啉单胞菌粘附素和牙龈卟啉菌蛋白酶对人Th 17细胞的调节。本研究的结果将有助于设计新的治疗靶点。

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.