Summary
This project aims to understand how changes in insulin epitopes and antigenicity drive Type 1 Diabetes (T1D) pathogenesis and to identify targets for immune modulation and therapeutic intervention by studying T-cell tolerance mechanisms.
Tuning peptide specifities for T cell tolerance in Type 1 diabetes
US · IL
NIH
grant
awarded
#nih-5R01DK133443-04
What they want
The project investigates the role of insulin as a dominant autoantigen in T1D, focusing on peptide binding characteristics within MHC Class II and recognition by autoreactive T cells. It proposes to use "super agonist" versions of insulin dominant epitopes and well-characterized mouse models, including TCR-transgenic lines, to define the role of central tolerance, characterize the effects of peripheral tolerance on insulin-reactive T cells, and explore mechanisms of dominant tolerance for potential therapeutic translation.
Deliverables
- Define the role of central tolerance upon the deletion of insulin-reactive clones
- Characterize the effects of peripheral tolerance on insulin-reactive T cells
- Explore mechanisms of dominant tolerance to understand the potential for translation into therapeutic treatments for T1D
- Gain a nuanced understanding of how changes in insulin epitopes and antigenicity drive the pathogenesis of diabetes
- Identify targets for future immune modulation and therapeutic intervention for T1D treatment and prevention
Technical requirements
- NOD mouse model of T1D
- MHC Class II peptide binding analysis
- Insulin gene modification (R to E variation in Ins2EE/+)
- Development of "super agonist" versions of insulin dominant epitopes
- Identification of the insulin-specific repertoire on key mouse backgrounds
- Utilization of TCR-transgenic mouse lines
