# Generating and Investigating Antigen-Deficient Islets in Autoimmune Diabetes

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2022 · $194,375

## Abstract

PROPOSAL SUMMARY
 Hybrid Insulin Peptides (HIPs) are a new family of autoantigens in Type 1 Diabetes (T1D). These peptides
form through covalent fusion of pro-insulin fragments to other beta-cell peptides. HIPs contain non-genomic
amino acid sequences, making them plausible targets for autoreactive T cells. We demonstrated that HIP-
reactive CD4 T cells trigger diabetes in non-obese diabetic (NOD) mice, are present in residual islets of organ
donors with T1D, and can be detected at significantly elevated levels in the peripheral blood of recent-onset
T1D patients. We also verified the presence of HIPs in human and murine islets by mass spectrometry. Our
data indicate that the protease Cathepsin D is responsible for the generation of HIPs that are targeted by
diabetes-triggering CD4 T cell clones. Here we will generate NOD mice carrying a mutation that prevents the
generation of HIPs. We predict that HIP-deficient beta-cells of these mice cannot be recognized by pathogenic
CD4 T cells and the mice will be protected from disease onset. We will analyze the islets of these mice to
assess HIP-content and T cell infiltration. We will also study disease incidence in these mice and determine
whether pathogenic CD4 T cell clones can transfer disease into these mice. Beta-cells, deficient of disease-
critical autoantigens, could allow us to reverse autoimmune diabetes in NOD mice and humans without the
need for immune-modulation or shielding of beta-cells through encapsulation.

## Key facts

- **NIH application ID:** 10493423
- **Project number:** 5R21AI166247-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** THOMAS DELONG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2021-09-22 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10493423

## Citation

> US National Institutes of Health, RePORTER application 10493423, Generating and Investigating Antigen-Deficient Islets in Autoimmune Diabetes (5R21AI166247-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10493423. Licensed CC0.

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