MECHANISMS OF ANTIBODY MEDIATED ATTENUATION OF BONE LOSS

我们已经证明了对猕猴的免疫 一种福尔马林固定的牙龈卟啉单胞菌细菌制剂 结果表明，小鼠血清中抗P. 牙周炎和牙槽骨破坏明显减轻。 通常情况下，细菌特异性血清抗体效价的增加 将有望减少受感染部位的细菌数量， 从而降低了疾病的严重程度。然而，DNA 对感染部位的探测分析显示，高病毒持续存在 牙龈假单胞菌的数量。这一观察结果提出了另一种选择 骨丢失的衰减机制。我们打算对此进行调查 通过比较免疫和非免疫血清在各种疾病中的可能性 体外功能测定。各种体外试验旨在 探讨细菌致突变的机制 炎症会导致组织和骨骼的破坏 已执行。精选细菌制剂的能力 牙龈假单胞菌和其他相关细菌刺激表达 几种已知的炎症和组织和骨骼破坏的介质 将会被检查。剂量/反应关系以及动力学 这些炎性介质的表达，将从 参与炎症反应的几种不同类型的细胞。 免疫和免疫前猴子血清的能力将进行比较 通过改变这些炎性介质的体外表达 细菌产品。如果发现封闭活性，单抗 将被产生以进一步定义和阐明 阻挡。这些实验的成功完成将澄清 炎症性疾病破坏性影响的一些细节 并阐明抗体作用的可能机制。 本项目建议的研究将在百时美施贵宝进行 达沃博士实验室的施贵宝药物研究所，地址： 该计划项目无需支付任何费用。

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.