MECHANISMS OF ANTIBODY MEDIATED ATTENUATION OF BONE LOSS

抗体介导的骨丢失减弱机制

• 批准号: 6270298
• 负责人: Richard Peters Darveau
• 金额: $ 4.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6270298
• 关键词: Bacteroides gingivalis; active immunization; antigen antibody reaction; antiserum; bacterial antigens; bone disorder; cell type; cytokine; gene expression; human subject; inflammation; laboratory mouse; lipopolysaccharides; monoclonal antibody; periodontitis

We have demonstrated that immunization of the Macaca fascicularis with a formalin-fixed bacterial preparation of Porphyromonas gingivalis resulted in a significant increase in the serum antibody titer to P. gingivalis and a significant reduction of alveolar bone destruction. Ordinarily, an increase in the bacteria-specific serum antibody titer would be expected to reduce the number of bacteria at infected sites, resulting in a decrease in the severity of the disease. However, DNA probe analysis of infected sites revealed the continued presence of high numbers of P. gingivalis. This observation suggests an alternate mechanism of bone loss attenuation. We intend to investigate this possibility by comparing immune and nonimmune sera in a variety of in vitro functional assays. A variety of in vitro assays designed to investigate the mechanism by which bacterially induced aberrant inflammation results in the destruction of tissue and bone will be performed. The ability of select bacterial preparations obtained from P. gingivalis and other relevant bacteria to stimulate expression of several known mediators of inflammation and tissue and bone destruction will be examined. Dose/response relationships, as well as the kinetics of expression of these inflammatory mediators, will be determined from several different cell types involved in the inflammatory response. Immune and preimmune monkey sera will be compared in their ability to alter the in vitro expression of these inflammatory mediators by bacterial products. If blocking activity is found, monoclonal antibodies will be generated to further define and elucidate the mechanism of blocking. The successful completion of these experiments will clarify some of the details of the destructive effect of the inflammatory response, as well as elucidate possible mechanisms of antibody action. Studies proposed in this Project will be performed at the Bristol-Myers Squibb Pharmaceutical Research Institute in Dr. Darveau's laboratory, at no cost to the Program Project.

我们已经证明了Macaca fascicularis的免疫 卟啉单胞菌的福尔马林固定细菌制剂 导致血清抗体滴度显着增加。 牙龈和牙槽骨破坏的显着减少。 通常，细菌特异性血清抗体滴度的增加 预计会减少受感染部位的细菌数量， 导致疾病的严重程度降低。 但是，DNA 对感染部位的探针分析表明，持续存在很高 牙龈疟原虫的数量。 该观察表明替代 骨质衰减的机制。 我们打算调查 通过比较各种免疫和非免疫血清的可能性 体外功能测定。 各种旨在的体外测定 研究细菌诱导异常的机制 炎症会导致组织和骨骼的破坏 执行。 从中获得的选择细菌制剂的能力 牙龈疟原虫和其他相关细菌刺激表达 炎症，组织和骨骼破坏的几个已知介体 将被检查。 剂量/响应关系以及动力学 这些炎症介质的表达将从 炎症反应涉及几种不同的细胞类型。 免疫和免疫前猴子血清的能力将被比较 改变这些炎症介质的体外表达 细菌产物。 如果发现阻断活性，则单克隆抗体 将生成进一步定义和阐明 阻塞。 这些实验的成功完成将澄清 炎症的破坏性作用的一些细节 反应，以及阐明抗体作用的可能机制。 该项目中提出的研究将在布里斯托尔美术馆进行 Darveau博士实验室的Squibb制药研究所在 该计划项目无需成本。