# Thymic and peripheral regulation of autoreactive T cells by coreceptor therapy

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $388,750

## Abstract

SUMMARY/ABSTRACT
Still needed are immunotherapies sufficiently robust to suppress β cell autoimmunity and safely prevent and
treat type 1 diabetes (T1D) in the clinic. This need is becoming more urgent in the face of an increasing
incidence of T1D in the United States and world-wide. We previously reported that a short-course of
nondepleting (ND) antibodies (Ab) specific for the T cell coreceptors CD4 and CD8α reverses diabetes in the
majority of new onset NOD mice, and that remission is indefinite. Self-tolerance is reestablished in a tissue-
specific manner and acquired immunity is unaffected. Notably, recent findings demonstrate that ND Ab specific
for human CD4 and CD8α engineered by our group exhibit similar tolerogenic properties in humanized mouse
models. Ongoing work has made the exciting observation that coreceptor therapy impacts both central and
peripheral tolerance, involving a number of novel mechanisms. Accordingly, the goal of this proposal is to
define the molecular and cellular events regulated by coreceptor therapy in the thymus and periphery that drive
long-term tissue-specific tolerance. In AIM 1, we will investigate the mechanisms by which coreceptor therapy
regulates the efficiency of thymic selection. In AIM 2, work will focus on determining how coreceptor therapy
influences T cell-mediated peripheral immunoregulation, and the pathogenicity of anti-self T cells. In both Aims,
experiments will exploit our ND anti-human CD4 and CD8α Ab to test the in vivo effects of coreceptor therapy
on thymocyte development and peripheral tolerance in humanized mice. Insight gained via the proposed
studies will establish treatment parameters for successful and safe clinical application of the approach.
Importantly, coreceptor therapy will be applicable not only for the prevention and treatment of T1D, but also for:
i) other T cell-mediated autoimmune diseases and pathologies, as well as ii) induction of transplantation
tolerance.

## Key facts

- **NIH application ID:** 9935026
- **Project number:** 5R01AI139475-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Roland M Tisch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2019-05-25 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935026

## Citation

> US National Institutes of Health, RePORTER application 9935026, Thymic and peripheral regulation of autoreactive T cells by coreceptor therapy (5R01AI139475-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9935026. Licensed CC0.

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