Local complement activation in inflammation & disease: therapeutic implications

炎症中的局部补体激活

• 批准号: 9281640
• 负责人: Georgios Hajishengallis
• 金额: $ 36.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9281640
• 关键词: Address; Adult; Affect; Alveolar Bone Loss; Atherosclerosis; Bacteria; C5a anaphylatoxin receptor; Cells; Chronic; Clinic; Clinical; Complement; Complement Activation; Complement Inactivators; Data; Development; Diabetes Mellitus; Disease; Focal Infection; Goals; Health; Histologic; Homeostasis; Human; Immune; Immune Targeting; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-17; Intervention; Investigation; Knockout Mice; Lead; Link; Lymphocyte; Macaca fascicularis; Mediating; Microbe; Microbial Biofilms; Modality; Modeling; Molecular; Monitor; Mucositis; Mucous Membrane; Mus; Pathogenesis; Pathway interactions; Periodicity; Periodontitis; Pharmaceutical Preparations; Porphyromonas gingivalis; Pre-Clinical Model; Production; Publishing; Receptor Cell; Refractory; Regulation; Rheumatoid Arthritis; Risk; Safety; Sampling; Sepsis; Shapes; Source; Specimen; Study models; Testing; Therapeutic; Therapeutic Intervention; Tissue Sample; Tissues; Toll-like receptors; Tooth Loss; Tooth structure; Translations; bone; bone loss; complement pathway; complement system; compstatin; conventional therapy; cytokine; design; experimental study; immune activation; in vivo; inflammatory bone loss; inhibitor/antagonist; innovation; insight; interleukin-23; knockout gene; microbial; microbial community; microbial host; microbiota; mouse model; mucosal site; nonhuman primate; pathogen; targeted treatment; γδ T cells

Complement can be produced locally or systemically and is a major link between infection and local or systemic inflammatory diseases, such as periodontitis or sepsis, respectively. However, little is known about local mechanisms that disrupt mucosal tissue-microbe homeostasis and set the stage for unwarranted complement activation. In this regard, periodontitis represents an attractive study model, as it is readily accessible for obtaining both microbial and host tissue samples to longitudinally investigate local inflammatory mechanisms. This highly prevalent disease (>47% of US adults) is initiated by a dysbiotic microbiota, leads to inflammatory destruction of tooth-supporting bone, and adversely affects systemic health in its severe form (8.5% of US adults). Periodontitis therefore urgently requires innovative treatments. The overarching concept in Project 3 of this POl is that complement is crucially and centrally involved in the initiation and amplification of destructive local inflammation in periodontitis through cross-talk interactions with the microbiota and other inflammatory pathways; hence, it represents a prime target for therapeutic intervention. Experiments have been designed to dissect the mechanisms of complement involvement in local tissue regulation of interieukin-17, a key cytokine produced by innate and adaptive immune cells and mediating inflammation and bone loss in periodontitis (Aim 1). On the basis of preliminary studies and those to be performed in Aim 1, appropriate complement inhibitors (Core B & Project 1) will be tested for their efficacy in treating periodontal inflammation and bone loss in non-human primates (Aim 2), a disease that shares key clinical and immunohistological features with human periodontitis. Local inflammation in this model will be investigated at the clinical, histological, and cellular/molecular level in a longitudinal approach that will also include periodic sampling of the periodontal biofilm to monitor complement-dependent dysbiosis. The C5a receptor (C5aR), a crucial target of microbial immune subversion leading to dysbiosis, and C3, required for the amplification of inflammation by the dysbiotic microbiota, will serve as initial targets of therapeutic intervention. Moreover, using a panel of pathway-specific inhibitors, we will dissect the initiation mechanism(s) leading to C3 activation and other complement pathways that may contribute to disease pathogenesis. Complement-specific drugs have already undergone successful safety trials, and promising interventions established in this project have potential for rapid translation to the clinic. Our longterm objective is to apply the mechanistic insights gained from studying local complement inflammation to the treatment of local infection-driven inflammatory diseases.

补体可以局部或全身产生，并且是感染和局部或全身性疾病之间的主要联系。 全身性炎性疾病，如牙周炎或败血症。然而，人们对 破坏粘膜组织-微生物稳态的局部机制， 补体激活在这方面，牙周炎代表了一种有吸引力的研究模型，因为它很容易 可获得微生物和宿主组织样本，以纵向研究局部 炎症机制。这种高度流行的疾病（>47%的美国成年人）是由一种微生态失调引起的。 微生物群，导致牙齿支撑骨的炎性破坏，并对全身健康产生不利影响 严重的形式（8.5%的美国成年人）。因此，牙周炎迫切需要创新的治疗。的 本政策说明书项目3的总体概念是，补体在 通过串扰相互作用引发和放大牙周炎中破坏性局部炎症 与微生物群和其他炎症途径;因此，它代表了治疗的主要目标。 干预已经设计了实验来剖析补体参与的机制， 白细胞介素-17的局部组织调节，白细胞介素-17是由先天性和适应性免疫细胞产生的关键细胞因子， 介导牙周炎中的炎症和骨丢失（目的1）。根据初步研究， 为了在目标1中进行，将测试适当的补体抑制剂（核心B和项目1）的 治疗非人灵长类动物牙周炎和骨丢失的功效（目的2）， 与人类牙周炎具有相同的临床和免疫组织学特征。局部炎症 模型将在临床、组织学和细胞/分子水平上进行纵向研究 这也将包括牙周生物膜的定期采样，以监测补体依赖性 生态失调C5 a受体（C5 aR）是导致生态失调的微生物免疫破坏的关键靶点， 和C3，由微生物群放大炎症所需，将作为初始目标 治疗干预。此外，使用一组途径特异性抑制剂，我们将剖析 导致C3激活的启动机制和其他可能有助于 发病机理补体特异性药物已经进行了成功的安全性试验， 该项目确定的有希望的干预措施有可能迅速转化为临床。我们的长期 目的是将从研究局部补体炎症中获得的机制见解应用于 局部感染驱动的炎症性疾病的治疗。