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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE007481-06
Application #
2129834
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1987-12-01
Project End
1996-05-31
Budget Start
1993-06-01
Budget End
1996-05-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Florida
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Karpinia, K A; Matt, M; Fennell 3rd, R S et al. (1996) Factors affecting cyclosporine-induced gingival overgrowth in pediatric renal transplant recipients. Pediatr Dent 18:450-5
Stutz, F A; Hefti, A F; Gibbs, C H (1996) Light source-induced error in computer-assisted image analysis with a video-based system. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:491-7
Hermann, J S; Rieder, C; Rateitschak, K H et al. (1995) Sonic and ultrasonic scalers in a clinical comparison. A study in non-instructed patients with gingivitis or slight adult periodontitis. Schweiz Monatsschr Zahnmed 105:165-70
Hassell, T M; Burtner, A P; McNeal, D et al. (1994) Oral problems and genetic aspects of individuals with epilepsy. Periodontol 2000 6:68-78
Hefti, A F; Eshenaur, A E; Hassell, T M et al. (1994) Gingival overgrowth in cyclosporine A treated multiple sclerosis patients. J Periodontol 65:744-9
Hefti, A F (1993) Aspects of cell biology of the normal periodontium. Periodontol 2000 3:64-75
Seymour, R A; Jacobs, D J (1992) Cyclosporin and the gingival tissues. J Clin Periodontol 19:1-11
Tullberg-Reinert, H; Hefti, A F (1991) Different inhibitory actions of cyclosporine A and cyclosporine A-acetate on lipopolysaccharide-, interleukin 1-, 1,25 dihydroxyvitamin D3- and parathyroid hormone-stimulated calcium and lysosomal enzyme release from mouse calvaria in vitro. Agents Actions 32:321-32
Hassell, T M; Hefti, A F (1991) Drug-induced gingival overgrowth: old problem, new problem. Crit Rev Oral Biol Med 2:103-37
Seibel, W; Yahia, N A; McCleary, L B et al. (1989) Cyclosporine-induced gingival overgrowth in beagle dogs. J Oral Pathol Med 18:240-5

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