T cells reactive to Hybrid Insulin Peptides (HIPs) as biomarkers of autoimmune diabetes An important objective in T1D research is the investigation of autoantigens that activate effector T cells and trigger the inflammatory process in islet beta-cells. We recently identified Hybrid Insulin Peptides (HIPs) as a new class of autoantigens in type 1 diabetes (T1D). These neoantigens are created by the fusion of insulin fragments with peptides from other secretory granule proteins such as chromogranin A (ChgA), islet amyloid polypeptide (IAPP), neuropeptide Y (NPY) or insulin itself. Because insulin is present only in pancreatic beta cells, this discovery might provide an explanation for organ-specific autoimmunity in T1D. Importantly, CD4 T cells responding to HIPs have been isolated from the islets of deceased T1D patients, demonstrating the relevance of these autoantigens to the human disease. We hypothesize that T cells reactive to HIPs can serve as biomarkers of disease. Our goals in this project are (1) to determine the HIP-reactive repertoire of CD4 T cells in NOD mice and (2) to determine the immunophenotype of HIP-reactive T cells in the PBMCs of T1D patients and controls. We will pursue these goals by analyzing T cell reactivity to a panel of HIP peptides in the NOD mouse model of T1D and by testing HLA-DQ8 tetramers loaded with HIP peptides for use in monitoring and selecting HIP-reactive T cells.

Public Health Relevance

Baker, UC Denver ? School of Medicine ? Dept. of Immunology and Microbiology This projects aims to gain better understating of T cell reactivity in the context of type 1 diabetes. Knowledge from these studies may improve our understanding of the underlying autoimmune disease process and may ultimately lead to better therapy that may change the course of this difficult clinical disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI133059-02
Application #
9616798
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Bourcier, Katarzyna
Project Start
2018-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
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; Jamison, Braxton L; Wiles, Timothy A et al. (2018) CD4 T Cells Reactive to Hybrid Insulin Peptides Are Indicators of Disease Activity in the NOD Mouse. Diabetes 67:1836-1846