# Engineering synthetic cellular crosstalk for transplantation tolerance

> **NIH NIH DP2** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $528,000

## Abstract

Organ transplantation remains the definitive treatment option for patients with end-stage organ
failure. Maintenance of functional allografts requires organ recipients to stay on immune-
suppressive drugs. However, most allografts have a limited lifespan because of the chronic
rejection initiated by the host alloimmune responses. The majority of immunosuppressive
treatments are targeted to the effector immune cells, such as T cells, leaving the root of
alloimmune responses—alloantigen presentation—untouched and leading to an immune
equilibrium which eventually is shifted toward graft rejection. Regulatory T cells (Tregs) with user-
defined specificity could be harnessed to induce immune suppression at desired tissues. They
also preserve the ability to tolerize antigen-presenting cells (APCs) through contact-dependent
cellular crosstalk. Our vision is to develop a robust allospecific immune regulatory strategy that
restricts alloimmune T cell responses at both the effector site (allograft) and the alloantigen
presentation site(graft draining lymphoid tissue) to shift the immune equilibrium to long-term
suppression in the allograft while keeping the remainder of the host immune system fully
operational. By leveraging the ability of chimeric antigen receptor (CAR) to recognize any desired
target and a lymph node targeting molecular vaccine to specifically deliver the target to lymph
node APCs, we will engineer an orthogonal synthetic vaccine to bridge crosstalk between CAR
Tregs and APCs via the CAR-directed interaction with its cognate bio-inert ligand synthetically
displayed on APCs. This synthetic vaccine-mediated crosstalk will have two outcomes: 1) APC-
to-CAR Treg signaling promotes CAR Treg expansion and migration to the allograft for targeted
suppression with enhanced regulatory functions. 2) CAR Treg-to-APC signaling tolerizes APC to
restrict alloreactive T cell priming and to promote the generation of induced regulatory T cells
(iTregs), which enforces a self-sustaining immunosuppression cycle via “infectious tolerance”. We
will evaluate the synthetic crosstalk in murine allotransplantation models. If successful, this
platform technology could be implemented across a broad landscape for precision control of
pathological conditions, including autoimmune diseases, graft-versus-host disease, and
transplant rejection.

## Key facts

- **NIH application ID:** 10295388
- **Project number:** 1DP2AI164319-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Leyuan Ma
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $528,000
- **Award type:** 1
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10295388

## Citation

> US National Institutes of Health, RePORTER application 10295388, Engineering synthetic cellular crosstalk for transplantation tolerance (1DP2AI164319-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10295388. Licensed CC0.

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