# Project 3:  Epitope Selection in Type 1 Diabetes

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $373,672

## Abstract

Project Summary/Abstract – Project 3 
Type-1 diabetes (T1D) is a serious autoimmune disease, whose incidence has been steadily 
increasing in recent years. It results from an immune attack on the pancreas by the patients T cells 
that selectively eliminates the insulin-producing beta cells that reside in the organs Islets of 
Langerhans eventually. The risk of developing T1D is tied to both environmental and genetic factors. 
The main genetic factor is tied to the polymorphisms in the genes encoding Class II molecules within 
the major histocompatibility gene complex (MHCII). 
 The usual function of MHCII molecules is usually to capture antigenic peptides derived from 
foreign proteins for presentation to and activation of CD4+ T cells in order direct these cells fight off 
infections. Since MHCII molecules can also capture and present peptides derived the host's own 
protein, the immune system has developed an elaborate two stage mechanism for preventing these 
self-peptides from inducing an autoimmune response against the hosts on tissues. The first stage 
involves a pre-check of CD4+ T cells in the thymus early in their development eliminating T cell whose 
antigen recognizing receptor (TCR) can engage an MHCII molecule containing a self-peptide. The 
second stage involves a set of regulatory T cells in the peripheral organs to deal with T cells that have 
somehow escaped the thymic pre-check. However, under the right conditions some of CD4+ T cells 
specific for certain peptides derived from pancreatic islet proteins sneak through both of these filters 
to cause T1D. The main objective of Project 3 is to determine why the T cells specific some 
pancreatic peptides are deleted in the thymus, while others are not, and to see if this information can 
be used to beef up the peripheral regulatory T cells to prevent the activation of the escapees. 
 In Project 3 our main hypothesis is that the thymic escapees recognize peptides that bind poorly in 
the thymus to the relevant MHCII risk alleles and therefore break through the thymic first filter. We 
will test this hypothesis by altering the expression of various pancreatic peptides in the thymus to see 
what effect this has on the appearance of CD4+ T cells of those specificities. We will also test the 
idea that by engineering the relevant peptide to bind better to the MHCII risk alleles we can create a 
“super agonist” that can be used to delete pathogenic T cells or to boost the activity of the peripheral 
regulatory T cells to prevent the activation of the pathogenic ones.

## Key facts

- **NIH application ID:** 9942374
- **Project number:** 5P01AI118688-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JOHN W KAPPLER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,672
- **Award type:** 5
- **Project period:** — → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942374

## Citation

> US National Institutes of Health, RePORTER application 9942374, Project 3:  Epitope Selection in Type 1 Diabetes (5P01AI118688-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942374. Licensed CC0.

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