# Immunological Tolerance to Hybrid Insulin Peptides

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2020 · $15,672

## Abstract

Project Summary
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 β-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 β-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 β-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.

## Key facts

- **NIH application ID:** 9841396
- **Project number:** 5F31DK113693-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Braxton Lochridge Jamison
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $15,672
- **Award type:** 5
- **Project period:** 2018-01-01 → 2020-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841396

## Citation

> US National Institutes of Health, RePORTER application 9841396, Immunological Tolerance to Hybrid Insulin Peptides (5F31DK113693-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9841396. Licensed CC0.

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