# Project 1: Next Generation Mixed Chimerism Strategies to Induce Lung Allograft Tolerance in NHPs

> **NIH NIH U19** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $1,319,385

## Abstract

PROJECT SUMMARY / ABSTRACT
Over 40% of lung allograft recipients succumb within five years of being transplanted, making it clear that there is an
urgent unmet need to address the inadequacies of chronic immunosuppression (IS) in these patients. Achieving a
robust state of tolerance in lung recipients would reduce or eliminate the major lung-specific and drug-related factors
that contribute to this dismal statistic. Tolerance of kidney allografts has been achieved in nonhuman primates (NHPs)
and humans by using a combination of nonmyeloablative conditioning and donor bone marrow transplantation that
results in transient mixed hematopoietic chimerism. However, identical protocols have failed to induce tolerance in
recipients of lung allografts. Despite the resistance of lung allografts to tolerance induction, we have now shown for
the first time, that achieving a state of durable (for the life of the organ) mixed chimerism in NHP recipients results in
long-term, IS-free survival of lung allografts. This remarkable result was achieved by modifying the mixed chimerism
conditioning to augment host regulatory mechanisms. While a significant advance, this modified mixed chimerism
protocol was only successful in recipients of MHC haplo-matched lung allografts and was associated with significant
toxicity in the form of posttransplant lymphoproliferative disease (PTLD), cytomegalovirus (CMV) infection, and
radiation-induced myelosuppression. Our goal now is to render this breakthrough clinically applicable by generating a
safer and more effective protocol that is capable of inducing long-term tolerance of unrelated, fully MHC mismatched
lung allografts using FDA-approved or soon-to-be-approved drugs. This Program’s unifying hypothesis is that inducing
durable chimerism and long-term tolerance in recipients of stringent lung allografts will require next-generation mixed
chimerism protocols that augment systemic and intra-graft adaptive and innate regulatory mechanisms. In Project 1,
we will 1) use intra-organ delivery of αIL-6R-specific nanoparticles to reduce the risk of acute rejection and IS-related
complications immediately following lung transplantation, 2) use mTORi-specific nanotherapies to achieve durable
chimerism and tolerance of lung allografts transplanted across a full MHC barrier by reducing trained immunity and
promoting regulatory mechanisms, and 3) incorporate Bcl-2 inhibition to promote durable mixed chimerism while
diminishing the toxicities related to αCD8 mAb treatment and total body irradiation (TBI). These studies will be
complemented by Project 2, which will test our unifying hypothesis using novel strategies for antibody-based
conditioning, regulatory T cells (Treg)-supportive immunomodulation, and gene-modified Tregs, all poised for
immediate clinical translation. State-of-the-art mechanistic assays coordinated by Core A (The Molecular Immunology
Core, ‘MIC’) will enable rapid cross-fertilization of insights gained in each project...

## Key facts

- **NIH application ID:** 10814262
- **Project number:** 5U19AI174967-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Joren C Madsen
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,319,385
- **Award type:** 5
- **Project period:** 2023-03-23 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814262

## Citation

> US National Institutes of Health, RePORTER application 10814262, Project 1: Next Generation Mixed Chimerism Strategies to Induce Lung Allograft Tolerance in NHPs (5U19AI174967-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814262. Licensed CC0.

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