# Project 2: Next-Generation Mixed Chimerism Induction for Heart Allograft Tolerance

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $646,162

## Abstract

PROJECT SUMMARY / ABSTRACT
Heart transplantation represents the best therapeutic option for patients with end-stage cardiac disease.
However, while one-year success rates are reasonable, heart transplant recipients encounter high rates of
morbidity and mortality, both from allograft rejection and from immunosuppression-associated toxicities. Given
these issues, the ultimate goal is immune tolerance induction, which promises life-long graft acceptance without
chronic immunosuppression. While tolerance to kidneys has been achieved in non-human primates (NHPs) and
in humans with transient mixed chimerism, the same protocols have failed to induce tolerance to heart (and lung)
allografts. Importantly, although lung allografts will not be studied in this Project, our recent findings in lung
recipients provide proof of principle that durable mixed chimerism can be achieved in NHP thoracic allograft
recipients which results in long term tolerance. This represents a major advance. However, this first success
employed agents that are not currently clinically available, and conferred ongoing risks of graft-versus-host
disease (GVHD) and of post-transplant lymphoproliferative disorder. These data, along with murine studies,
suggest that durable mixed chimerism represents a robust platform for thoracic organ tolerance induction, but
that improved strategies are needed, with a focus on preventing GVHD, preserving protective immunity, and
rapid clinical translation. In this Project, we will address three major hurdles in translating durable chimerism-
based strategies for heart transplant tolerance to the clinic: (A) Controlling graft versus host disease (GVHD)
during chimerism-induction; (B) Developing novel methods of recipient conditioning that are non-genotoxic; and
(C) Inducing chimerism using the safest and most efficiently engrafting subset of hematopoietic stem cells. We
will do so by completing the following Specific Aims: Specific Aim 1: To induce durable mixed chimerism, optimize
Treg homeostasis and preserve protective immunity with OX40L blockade and mTOR inhibition. Specific Aim
2: To develop toxicity-free induction by using antibody-drug conjugate (ADC)-based non-genotoxic conditioning
to induce durable mixed-chimerism and transplant tolerance. Specific Aim 3: To induce durable chimerism with
a highly purified subset of stem cells capable of rapid multilineage engraftment. If successful, this project will
optimize durable chimerism induction strategies for heart allograft tolerance, amenable to immediate clinical
translation.

## Key facts

- **NIH application ID:** 10457401
- **Project number:** 5P01HL158504-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Leslie S Kean
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $646,162
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457401

## Citation

> US National Institutes of Health, RePORTER application 10457401, Project 2: Next-Generation Mixed Chimerism Induction for Heart Allograft Tolerance (5P01HL158504-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10457401. Licensed CC0.

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