Insulin-diabetes mellitus (IDDM) results from autoimmune destruction of the insulin-producing pancreatic beta-cells. The development of IDDM is dependent upon the activation of T cells specific for islet antigens. These cells migrate to the islets of Langerhans in the pancreas and accumulate there before eventually destroying the islet beta-cells. The long term goal of this project is to define how the conditions of T cell activation influence the generation of diabetogenic beta-cell specific effector cells. To examine the conditions required for T cell priming, a simplified murine transgenic model has been adapted whereby naive T cell receptor (TCR) transgenic CD4+ cells are activated with specific peptide (ovalbumin) under defined conditions in vitro prior to adoptive transfer into mice expressing ovalbumin in the pancreas.
In Aim I, experiments are proposed to determine the role of ligand density in generating effector cells able to migrate to the pancreas and destroy beta cells. Preliminary studies indicate that CD4+-cells stimulated only with low and not high concentrations of peptide induce IDDM in recipient mice. Emphasis will be placed on determining whether T cells activated with high concentrations of antigen are unusually sensitive to immunoregulation and on defining the particular immunoregulatory mechanisms involved.
In Aim II, the role of accessory molecule interactions in priming diabetogenic effector cells will be examined. Experiments are proposed to define how interactions involving ICAM-1 promote generation of pathogenic effector cells and how activation of CD4+ cells via B7.1 vs. B7.2 costimulatory molecules alters the functional capacities of those cells in vivo. These studies will provide new information regarding the conditions of priming that lead to the generation of diabetogenic effector CD4+ cells and may prove useful in devising strategies for intervention in diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK057644-03
Application #
6589291
Study Section
Special Emphasis Panel (ZDK1)
Project Start
2002-06-01
Project End
2003-05-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
$221,356
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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