Mast Cell Effects on Islet Cell Destruction in NOD Mice

DESCRIPTION (provided by applicant): Mast cells are potent inflammatory cells that have been best studied in the realm of allergy research. Recent evidence has established a role for mast cells in murine models of autoimmune diseases such as multiple sclerosis and arthritis. Mast cells are normally present in the pancreas and increase in numbers in inflammatory conditions of the pancreas such as pancreatitis. In addition, they are important producers of mediators that are known to regulate T cell responses that initiate the inflammation that contributes to diabetes. It is hypothesized that mast cells influence inflammatory events that lead to pancreatic islet beta cell destruction. To test this, we will utilize a mast cell-deficient mouse model. Genes that give rise to a mast cell-deficient phenotype (two distinct ckit mutations) will be bred onto the NOD/Lt mouse background and the effects on indices of pre-diabetes and diabetes will be evaluated. The specific aims are: 1. To develop and characterize a line of mast cell-deficient NOD mice 2. To examine the consequencess of mast cell-deficiency on the development of spontaneous insulitis and diabetes. 3. To determine the sites of mast cell influence on diabetes development.