The global hypothesis underlying this project is that interactions between natural killer (NK) cells and monocytes/macrophages (MO) are important in human defense against invading periodontopathogens. Because these cells are not restricted by the major histocompatibility complex, they are capable of a prompt response to many stimuli. By testing the interactions of lipopolysaccharides (LPS) from pathogenic and non-pathogenic oral bacteria with NK cells and MO, this project will examine NK and MO killing mechanisms and cellular regulation. It will also address the potential of cellular regulatory molecules to participate in bone destruction, a hallmark of periodontal disease. This project will focus on fundamental aspects of the pathogen-NK/MO interaction which should provide valuable information on the pathogenesis of periodontal disease. Understanding the nature of cytotoxic regulatory processes may permit the manipulation of these processes in a predictable manner for the benefit of the affected patient. To specifically address the issues of NK and MO regulation in periodontal disease, four hypotheses will be tested: 1) that NK down-regulation by LPS-stimulated MO occurs due to the production of an active intermediary, such as prostaglandins, interleukin-1 (IL-1), or tumor necrosis factor (TNF), 2) that antibodies against NK and MO adherence molecules (LFA antigens) provide a negative signal thereby blocking interferon (IFN) release by LPS and other stimulators known to induce IFN, 3) that LPS-activated NK cells and MP participate in direct killing of periodontal bacteria, and 4) that LPS from pathogenic and non-pathogenic periodontal bacteria induce dissimilar IL-1 and TNF gene expression in MO.
