MECHANISMS OF ANTIBODY MEDIATED ATTENUATION OF BONE LOSS

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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.