Salivary gland dysfunction results from dietary changes, radiation therapy, aging, certain medications and viral or genetic diseases. The loss of gland function and thus saliva production results in the clinical manifestation of xerostomia or """"""""dry mouth."""""""" Some autoimmune diseases of man, for example, Sjogrens syndrome and Type 1 diabetes (IDD), show progressive lymphocytic infiltration of the salivary glands with a subsequent reduction in saliva synthesis and secretion. IDD is characterized by autoimmune destruction of insulin producing beta cells of the pancreas. Further investigations have revealed that in diabetic patients and the NOD (non-obese diabetic) mouse, lymphocytic infiltration of exocrine tissues, including the submandibular gland, is common. One metabolic complication of human autoimmune IDD is xerostomia with associated increases in caries and potential periodontal disease development. To date, development of an adequate animal model for the analysis of autoimmune induced salivary gland dysfunction would facilitate the study of xerostomia. Using the NOD mouse, we recently observed that with the progressive autoimmune reaction against beta cells, lymphocytes simultaneously infiltrated into the parotid and submandibular glands of diabetic and pre-diabetic animals. This was accompanied by a corresponding decline in stimulated flow rates and loss of specific secretory protein biosynthetic capacity. These observations suggest that salivary gland dysfunction is not due to an acute inflammatory response caused by lymphocytic infiltration and cellular destruction, but more accurately reflects changes due to the chronic lymphocytic activation present in the autoimmune pathology. Therefore, we propose here to investigate the autoimmune sialoadenitis of the NOD mouse to determine its potential as an animal model for autoimmune-induced xerostomia. Specifically, we plan to 1) Characterize the autoimmune reaction against salivary glands leading to xerostomia; 2) Determine changes in the level of membrane receptors and intracellular components of the signal transduction pathways which are commonly activated during the secretory process and 3) Characterize the role of insulin-like peptides on parotid gland function at onset of autoimmune sialoadenitis in IDD. Results from these studies should provide insights into autoimmune responses that traditionally lead to salivary gland dysfunction with obvious clinical and dental relevance. In addition, we anticipate that the NOD mouse will prove to be a useful model for developing our understanding of Sjogrens syndrome, Rheumatoid arthritis and Type 1 IDD; diseases in which the autoimmune pathology causes a loss of protective salivary secretions with the resulting patient discomfort associated with xerostomia and increased caries, periodontal disease and aggravation of oral mucosa and soft tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE010515-02
Application #
2131399
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1994-04-01
Project End
1998-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
2
Fiscal Year
1995
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
Brayer, J B; Cha, S; Nagashima, H et al. (2001) IL-4-dependent effector phase in autoimmune exocrinopathy as defined by the NOD.IL-4-gene knockout mouse model of Sjogren's syndrome. Scand J Immunol 54:133-40
Cha, S; van Blockland, S C; Versnel, M A et al. (2001) Abnormal organogenesis in salivary gland development may initiate adult onset of autoimmune exocrinopathy. Exp Clin Immunogenet 18:143-60
Brayer, J; Lowry, J; Cha, S et al. (2000) Alleles from chromosomes 1 and 3 of NOD mice combine to influence Sjogren's syndrome-like autoimmune exocrinopathy. J Rheumatol 27:1896-904
Yamachika, S; Brayer, J; Oxford, G E et al. (2000) Aberrant proteolytic digestion of biglycan and decorin by saliva and exocrine gland lysates from the NOD mouse model for autoimmune exocrinopathy. Clin Exp Rheumatol 18:233-40
Humphreys-Beher, M G; Peck, A B (1999) New concepts for the development of autoimmune exocrinopathy derived from studies with the NOD mouse model. Arch Oral Biol 44 Suppl 1:S21-5
Humphreys-Beher, M G; Brayer, J; Yamachika, S et al. (1999) An alternative perspective to the immune response in autoimmune exocrinopathy: induction of functional quiescence rather than destructive autoaggression. Scand J Immunol 49:7-10
Yamachika, S; Nanni, J M; Nguyen, K H et al. (1998) Excessive synthesis of matrix metalloproteinases in exocrine tissues of NOD mouse models for Sjogren's syndrome. J Rheumatol 25:2371-80
Robinson, C P; Bounous, D I; Alford, C E et al. (1998) Aberrant expression and potential function for parotid secretory protein (PSP) in the NOD (non-obese diabetic) mouse. Adv Exp Med Biol 438:925-30
Robinson, C P; Brayer, J; Yamachika, S et al. (1998) Transfer of human serum IgG to nonobese diabetic Igmu null mice reveals a role for autoantibodies in the loss of secretory function of exocrine tissues in Sjogren's syndrome. Proc Natl Acad Sci U S A 95:7538-43
Robinson, C P; Cornelius, J; Bounous, D E et al. (1998) Characterization of the changing lymphocyte populations and cytokine expression in the exocrine tissues of autoimmune NOD mice. Autoimmunity 27:29-44

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