In Type 1 Diabetes (T1D) it is well recognized that autoreactive CD4 and CD8 T cells infiltrate the pancreatic islets leading to the destruction of insulin-producing ?-cells. We recently found that CD4 T cell clones isolated from non-obese diabetic (NOD) mice and humans with T1D recognize hybrid insulin peptides (HIPs) that consist of proinsulin peptides fused to other peptides present in ?-cell secretory granules. Our data suggest that HIPs play a central role in the pathogenesis of T1D and we hypothesize that a loss of immune tolerance in HIP-reactive T cells is responsible for loss of tolerance to the pancreatic islets as a whole. However, the factors that cause a loss of tolerance in T cells targeting HIPs are unknown. We also predict that HIPs will be optimal for use in antigen-specific tolerance induction strategies compared to conventional ?-cell autoantigens.
Our aims will be to i) investigate how disease-susceptibility background genes contribute to a loss of tolerance in HIP-reactive CD4 T cells, and ii) determine if induction of tolerance to HIPs can prevent and reverse diabetes in NOD mice. To investigate how susceptibility genes other than MHC loci contribute to a loss of tolerance we will compare HIP-reactive T cell responses in NOD and diabetes-resistant mice that express the NOD MHC class II haplotype H-2g7 but do not carry susceptibility background genes (B6g7 mice). Understanding how HIP- reactive T cells are regulated in non-autoimmune B6g7 mice and how this fails in NOD mice is critical to understanding the pathophysiology of T1D. To determine if HIPs can be effectively used for antigen-specific tolerance induction, we are developing biodegradable nanoparticles loaded with HIPs. We plan to test the ability of HIP-loaded nanoparticles to prevent disease transfer by diabetogenic T cells and reverse spontaneous disease in NOD mice. These studies are likely to have a significant and lasting impact on T1D research and could potentially lead to the development of novel antigen-specific therapeutics.

Public Health Relevance

Understanding why and how autoreactive T cells attack insulin-producing ?-cells in Type 1 Diabetes (T1D) is necessary for the development of next-generation therapeutics that can stop the disease process. We have recently discovered a new family of autoantigens that may explain how ?-cells become a target for T cells and how T1D is triggered. This project is to investigate the function of T cells reactive to these antigens and whether therapeutic reagents containing these antigens can prevent or reverse diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DK113693-02
Application #
9624353
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Rivers, Robert C
Project Start
2018-01-01
Project End
2021-08-31
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