# Exploitation of PD1-mediated tolerogenic signals for the treatment of SLE

> **NIH NIH R21** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $231,000

## Abstract

PD-1 is an inhibitory receptor induced in T cells after activation and regulates the balance between stimulatory
and inhibitory signals that plays a vital role in the induction and maintenance of anergy and peripheral tolerance.
By inhibiting T effector cell function, PD-1 signaling mediates tissue tolerance by suppressing tissue-reactive T
cells and protects against immune-mediated tissue damage. PD-1 can also regulate T cell tolerance by
promoting the generation of Treg cells. PD-1 requires proximity and co-ligation with the TCR, resulting in tyrosine
phosphorylation of the ITSM motif in C-terminus of PD-1 cytoplasmic tail leading to the recruitment of SHP-2 and
inhibition of multiple downstream activation pathways. Our recent work has provided mechanistic insights of how
PD-1-TCR/CD3 co-ligation affects T cell signaling pathways that mediate induction of anergy, alters metabolic
reprogramming and impacts the differentiation program of T effector cells. In the present exploratory application,
we will test a novel hypothesis that co-ligating PD-1 and TCR is a novel approach to suppress aberrantly
activated T cells. To this end, we will generate a single chain diabody termed PD1-scDb to co-engage PD-1 and
TCR/CD3 to suppress T cell activation. This conceptually and technically novel approach is in stark contrast
to the mainstream current approaches, which aim to block PD-1-mediated inhibitory signaling with the goal to
enhance T cell activation. To demonstrate the potential therapeutic application of our novel compound to tame
aberrantly activated T cells we will test its ability to reverse the signaling, metabolic and functional aberrations of
autoreactive T cells and ameliorate symptoms of systemic lupus erythematosus (SLE), the prototype
autoimmune disease. For this purpose we generated a prototype hPD1-scDb that showed potent inhibition of T
cell responses, providing proof-of-concept of our novel idea and feasibility of our technical innovation. In our
present proposal, we will use hPD1-scDb to investigate the molecular and biochemical mechanisms of its
function and its ability to suppress responses of autoreactive T cells from patients with SLE. We will also generate
a mouse (m) PD1-scDb and investigate its immunosuppressive properties in vitro and in vivo using mouse
models of SLE.
To achieve our goals we will pursue the following specific aims:
SA1. To determine the effects of mPD1-scDb ex vivo and in vivo using mouse models of SLE.
SA2. To identify the effects of hPD1-scDb on T cells from patients with SLE.

## Key facts

- **NIH application ID:** 10007753
- **Project number:** 5R21AR073494-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Nikolaos Patsoukis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $231,000
- **Award type:** 5
- **Project period:** 2019-09-04 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007753

## Citation

> US National Institutes of Health, RePORTER application 10007753, Exploitation of PD1-mediated tolerogenic signals for the treatment of SLE (5R21AR073494-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10007753. Licensed CC0.

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