A number of recent studies from our laboratory have provided convincing evidence that the immune system plays a role in the genesis of many chronic periodontal diseases. However, the precise mechanism(s) whereby these diseases develop and progress is not yet clear. In this application we propose to examine the role played by various cell types from human gingival tissue in regulating the immunopathology of periodontitis. Specifically, we propose to: (1) to determine whether gingival fibroblasts modulate both the lymphocyte responsiveness and T lymphocyte differentiation to antigens which are known to be involved in human periodontal disease, (2) to determine if fibroblasts, like macrophages, can release toxic mediators and thereby influence the immune response at sites of inflammation, (3) to determine if a cell adhesion molecule (ELAM-1) which is expressed on human gingival fibroblasts is involved in lymphocyte-fibroblast interactions and (4) to examine the regulatory role played by monocyte-derived inflammatory macrophages (mphi) in the development and progression of periodontitis. To achieve these objectives we propose a set of systematic investigations using purified populations of lymphocytes, monocytes and gingival tissues from both humans and rats as a model system. Emphasis will be placed on identifying the regulatory signals, namely lymphokines, which are released by stimulated macrophages and which modulate the growth of plaque-forming cells in vitro. The latter investigations will utilize antigen-specific and antigen-nonspecific factors such as interferon gamma (IFN-gamma), colony stimulating factor and granulocyte-macrophage colony-stimulating factor (CSF). We will use recombinant DNA technology to generate transgenic mice which over-express IFN-gamma and a "transforming" factor designated interleukin 10 (IL-10). These mice will be used to generate animal models of disease. The long-term objective is to examine the effects of these genetically altered animals in order to gain an understanding of the manner in which these regulatory molecules, derived from lymphocytes and/or macrophages, contribute to the immunopathology associated with chronic gingivitis. Collectively, these studies will provide a new paradigm for the development and progression of human periodontal disease and suggest new therapeutic approaches.