The objective of this revised proposal is to identify immune response mechanisms which are important to the development of autoimmunity against the pancreatic beta cells. There have been major breakthroughs in our understanding of the normal human immune response with respect to the molecular genetics of HLA molecules and their role in antigen presentation, molecular cloning and characterization of the T-cell receptor, the molecular genetics of immunoglobin genes and the control of antibody formation, as well as the identification of a large number of cyto- and lymphokines with multiple biological functions. A coordinated mulltidisciplinary approach taking into account these different key functions of the immune response is yet to be carried out in order to understand the autoimmune response which may be responsible for the specific eradication of the pancreatic beta cells in insulin-dependent diabetes. In this program project we shall test whether the loss of pancreatic beta cells is dependent on a pattern of interacting immunologic mechanisms. Specifically, we will elucidate whether this disease involves abnormalities in 1) beta cell antigen biosynthesis and/or expression and the effects of insulin secretagogues and inflammatory mediators; 2) processing and MHC- restricted presentation of beta cell antigens; 3) the activation of specific T cell responses characterized by a restricted use of T cell receptor genes; 4) the formation of autoantibodies by a restricted use of immunoglobulin genes and 5) the in vivo control of the inflammatory cell reactivity in and around the pancreatic islets. The pathophysiologic significance of these genetic and immune markers will be tested in shared patient and control populations and in transgenic mice or experimental animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
1P01DK041801-01A1
Application #
3095586
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1990-09-20
Project End
1995-02-28
Budget Start
1990-09-20
Budget End
1991-05-31
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Falorni, A; Kockum, I; Sanjeevi, C B et al. (1995) Pathogenesis of insulin-dependent diabetes mellitus. Baillieres Clin Endocrinol Metab 9:25-46

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