# Thyroid Derived Peptide Presentation by HLA-DR in Thyroiditis

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $113,528

## Abstract

I. RESEARCH PLAN OF THE PARENT GRANT
A) SUMMARY OF THE PARENT GRANT
Autoimmune thyroid diseases (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis
(HT) are currently treated only symptomatically and not by targeting the mechanisms causing
disease. Our long-term goal is to design precision-targeted therapies for AITD by blocking
presentation of thyroidal antigens to T-cells. In order to block antigen presentation, we are
targeting HLA-DRb1-Arg74, which we have previously shown to be the key HLA-DR pocket that
presents thyroidal peptides triggering AITD. During the last grant period we made significant
progress towards our long-term goals: (1) We identified the key TSHR peptide epitope causing
GD; (2) We identified Cepharanthine as a compound that blocks DRb1-Arg74 and prevents AITD
in a mouse model; (3) We identified D-peptides that block peptide binding to DRb1-Arg74; (4)
Using genome-wide approaches we identified new AITD susceptibility genes (e.g. ARID5B); (5)
We identified genetic-epigenetic interactions triggering AITD. Building on the progress made in
the previous grant period we propose to develop new therapeutic approaches for AITD by
blocking antigen presentation. Our hypothesis is that presentation of pathogenic Tg/TSHR
peptides to T-cells within the DRb1-Arg74 pocket we discovered is key to triggering AITD, & that
blocking peptide binding to this pocket can be used to treat/prevent AITD. Our specific aims are:
Specific Aim 1: We will enhance the potency and efficacy of Cepharanthine in blocking antigen
presentation within DRb1-Arg74 by creating modified Cepharanthine analogs (MCA's). We will
use in silico methods to design MCA's; MCA's will be confirmed using our uniquely designed
ELISA and cell-based assays, and using ex vivo and in vivo experiments in “humanized” DR3
mice in which we will induce autoimmune thyroiditis.
Specific Aim 2: We will generate monoclonal antibodies (MAb's) targeting the HLA-DRb1-Arg74
– Tg.2098 complex. This approach is based on our findings that presentation of the Tg peptide
Tg.2098 by DRb1-Arg74 is the key step in triggering AITD. The MAb's we produce will be
screened by our in vitro ELISA and cell-based assays, and confirmed ex vivo and in vivo in our
DR3 “humanized” mouse model of AITD.
Specific Aim 3: We will validate that MCA's & MAb's block antigen presentation in patients with
AITD. We will validate MCA's and MAb's by testing their ability to inhibit T cell recall responses
to thyroidal antigens in peripheral blood mononuclear cells (PBMC's) isolated from AITD patients
that are positive for DRb1-Arg74.
In summary, our multidisciplinary translational project builds on the knowledge gained in the
previous grant period. Our goal is to pursue preclinical development of novel therapies for AITD
based on blocking antigen presentation by HLA-DRb1-Arg74. Our collaborative team has the
capacity, experience, & expertise to achieve the aims of our proposal. The main advantage of our
therapeutic a...

## Key facts

- **NIH application ID:** 10175939
- **Project number:** 3R01DK073681-12S1
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** YARON TOMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $113,528
- **Award type:** 3
- **Project period:** 2020-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10175939

## Citation

> US National Institutes of Health, RePORTER application 10175939, Thyroid Derived Peptide Presentation by HLA-DR in Thyroiditis (3R01DK073681-12S1). Retrieved via AI Analytics 2026-07-19 from https://api.ai-analytics.org/grant/nih/10175939. Licensed CC0.

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