# Studying and regulating trained immunity in mouse transplant models

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $919,879

## Abstract

SUMMARY – PROJECT 2
Transplantation has revolutionized the lives of patients suffering from organ failure. However, the associated
immunosuppressive therapies induce significant side effects and display suboptimal success rates. Achieving a
state of operational tolerance would lead to indefinite graft survival without chronic immunosuppression and its
associated morbidity. This P01’s investigators have revealed pronounced organ-specific differences in
tolerance induction, preserved across species. For example, kidney and liver allografts are easier to tolerize
than heart and lung allografts. Moreover, co-transplanting a kidney promotes tolerance of heart allografts. These
phenomena indicate an underappreciated mechanism regulating allograft tolerance, which might be
therapeutically leveraged to turn “tolerant resistant” into “tolerance prone” organs.
This P01’s investigators have also demonstrated that trained immunity plays a critical role in allograft
rejection. Trained immunity is a long-term (>several months) increased functional responsiveness of innate
immune cells mediated through epigenetic mechanisms at the level of hematopoietic progenitors in the bone
marrow, resulting in enhanced production of hyperresponsive myeloid cells. We demonstrated that
transplantation induces trained immunity and that the ensuing ‘trained’ myeloid cells promote graft rejection.
Project 2’s premise is 1) that the difference between organs’ susceptibility to acute rejection stems from
different degrees or modes of trained immunity of trained immunity and that 2) therapeutically inhibiting
trained immunity early post-transplantation will prolong graft survival. In line with this, we have developed
bone marrow-avid nanotherapeutics which inhibit the trained immunity regulator mTOR and effectively promote
allograft survival without continuous immunosuppressive therapy.
Here, we propose studying and therapeutically inhibiting trained immunity in mouse transplant models. Aim 1
will longitudinally assess the (innate) immune response to rejecting heart and spontaneously accepting kidney
transplantation, using in vivo immuno-PET imaging and ex vivo (multi-omics) analyses. We will strive to maximize
the obtained mechanistic insights using relevant knockout models and syngeneic controls. In parallel, Aim 2 will
therapeutically inhibit trained immunity-related metabolic and epigenetic pathways and similarly study the effects
on the immune system and graft survival.
This Project will unravel the mechanisms behind transplantation-induced trained immunity and its role in graft
rejection. Furthermore, it will advance an innovative treatment paradigm based on trained immunity-regulating
nanobiologics and initiate clinically relevant readouts of trained immunity based on immuno-PET imaging.
Project 2, led by Dr. Teunissen, will interface with Projects 1 and 3 by providing mechanistic insights and
validating novel therapeutic targets.

## Key facts

- **NIH application ID:** 10851853
- **Project number:** 5P01AI168258-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Abraham Teunissen
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $919,879
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851853

## Citation

> US National Institutes of Health, RePORTER application 10851853, Studying and regulating trained immunity in mouse transplant models (5P01AI168258-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10851853. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*