With respect to research on type 1 diabetes (T1D), a major gap in the field has been the lack of reagents for the induction of antigen-specific tolerance. Identification of the beta-cell autoantigens that drive the pathogenic T cells in this disease has been a top priority for researchers since knowledge of these proteins could add considerably to our understanding of how diabetes develops, including the relative importance of antigens arising at different stages of disease. To identify antigens for a long- established panel of highly diabetogenic, NOD-derived T cell clones, we have used biochemical separation procedures and proteomic analysis to isolate proteins from islet beta-cells. This work has led to the recent discovery of a new autoantigen in T1D, the secretory granule protein, chromogranin A. The underlying hypothesis of this project is that the antigenic ligands for this panel of diabetogenic clones are derived from a set of closely related proteins and are generated through a common mechanism. To test this hypothesis, we have designed a project in which our goals are to identify antigens for diabetogenic T cells, define the mechanisms by which they arise, and characterize their biological relevance to disease.
Our aims are to: (1) isolate the 2-cell antigens for islet- reactive, diabetogenic CD4 T cell clones, (2) determine the primary structure, including modifications, of antigenic peptides, and (3) determine whether WE14, a peptide from ChgA, can be used as a tolerogen to prevent or delay T1D. Expanding our knowledge of the proteins that are the sources of T cell peptide antigens will allow us to better understand their significance in T1D, and will provide the basis for specific therapeutic intervention at the level of the T cell. These proteins, and the peptide ligands from them, will provide information about autoimmune mechanisms, can be used for induction of antigen-specific tolerance or serve as targets for drug intervention, and may also assist in developing methods for early diagnosis and monitoring disease progression.

Public Health Relevance

Expanding our knowledge of the proteins that are antigens for autoreactive T cells will allow us to better understand their significance in T1D and will provide the basis for specific therapeutic intervention at the level of the T cell. Proteins identified to be T cell autoantigens will provide information about autoimmune mechanisms, can serve as targets for drug intervention, and may also assist in developing methods for early diagnosis and monitoring disease progression. In addition, knowledge of the biological function of the autoantigenic targets may itself provide new insight into 2-cell function in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081166-03
Application #
8448588
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Sechi, Salvatore
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$458,292
Indirect Cost
$121,199
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Baker, Rocky L; Bradley, Brenda; Wiles, Timothy A et al. (2016) Cutting Edge: Nonobese Diabetic Mice Deficient in Chromogranin A Are Protected from Autoimmune Diabetes. J Immunol 196:39-43
Wiles, Timothy A; Delong, Thomas; Baker, Rocky L et al. (2016) An insulin-IAPP hybrid peptide is an endogenous antigen for CD4 T cells in the non-obese diabetic mouse. J Autoimmun :
Delong, Thomas; Wiles, Timothy A; Baker, Rocky L et al. (2016) Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351:711-4
Babon, Jenny Aurielle B; DeNicola, Megan E; Blodgett, David M et al. (2016) Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes. Nat Med 22:1482-1487
Gottlieb, Peter A; Delong, Thomas; Baker, Rocky L et al. (2014) Chromogranin A is a T cell antigen in human type 1 diabetes. J Autoimmun 50:38-41
Cordova, Kristen N; Willis, Van C; Haskins, Kathryn et al. (2013) A citrullinated fibrinogen-specific T cell line enhances autoimmune arthritis in a mouse model of rheumatoid arthritis. J Immunol 190:1457-65
Baker, Rocky L; Delong, Thomas; Barbour, Gene et al. (2013) Cutting edge: CD4 T cells reactive to an islet amyloid polypeptide peptide accumulate in the pancreas and contribute to disease pathogenesis in nonobese diabetic mice. J Immunol 191:3990-4
Reisdorph, N; Wechsler, M E (2013) Utilizing metabolomics to distinguish asthma phenotypes: strategies and clinical implications. Allergy 68:959-62
Delong, Thomas; Baker, Rocky L; He, Jing et al. (2013) Novel autoantigens for diabetogenic CD4 T cells in autoimmune diabetes. Immunol Res 55:167-72
Hume, Patrick S; He, Jing; Haskins, Kathryn et al. (2012) Strategies to reduce dendritic cell activation through functional biomaterial design. Biomaterials 33:3615-25

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