This application requests continuation of support for studies of the gingival fibrosis and enlargement elicited in man by the selective immunosuppressant drug cyclosporine-A (CsA). CsA has been available in the USA since 1983, and is used primarily in solid organ and bone marrow transplant patients to prevent graft rejection. It is also used in the treatment of type I diabetes mellitus, multiple sclerosis, rheumatoid arthritis and many other autoimmune diseases. In addition to the gingival side effect, CsA also causes interstitial fibrosis in renal and pericardial tissues. The experiments proposed will investigate mechanisms of such pathology. A multinational epidemiologic study, begun in years 01-03, will be completed, with the participation of 400 human subjects. A novel 3-dimensional laser scanner has been developed and can now be employed for the precise measurement of tissue contours in the .oral cavity of such patients. This study will provide basic information concerning inCidence of the lesions, as well as therapeutic and preventive strategies. In vitro experiments will utilize human gingival fibroblast subpopulations that will be discriminated and sorted by means of fluorescence activation after exposure to dansylated CsA. CsA sensitive and CsA nonsensitive subsets will be characterized according to their biochemical behavior in culture (e.g., production of protein, collagen and glycosaminoglycans, DNA), their response to in vitro CsA challenge, and their ability to attach to and migrate upon a substrate. Characterized fibroblast populations will be analyzed for the presence of nuclear and cytosolic receptors for CsA (cyclophilins), and such receptors will be characterized. The possible involvement of products of the host immune response in the etiology of gingival enlargement will also be addressed in vitro , in a series of experiments with various cytokines alone and in combination with CsA. Successful completion of the proposed research should provide new knowledge that will benefit physicians and dentists, and that will help to elucidate cellular and molecular mechanisms of human connective tissue pathology.
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