# Myeloid Specific Targeted Nanoimunotherapy for Organ Transplant Acceptance

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $572,859

## Abstract

SUMMARY
Induction of graft acceptance in the absence of chronic immunosuppressive therapy remains an elusive goal in
organ transplantation. Transplant immunologists have historically attempted to prevent organ rejection by
developing novel therapeutic approaches that target antigen-presentation (signal 1), co-stimulation (signal 2)
and/or cytokine production (signal 3). While promising results have been obtained using these novel
methodologies that target the adaptive immune response, long-term graft survival rates remain suboptimal.
Recent data demonstrates that the innate immune system (macrophages) initiate transplant rejection. In line
with these observations, our laboratory has recently discovered a novel pathway that contributes to allograft
rejection, which is mediated by epigenetic reprograming of macrophages. This recently discovered
macrophage functional state has been defined as “trained immunity” and is positively regulated by the
mammalian target of rapamycin (mTOR). While regulation of macrophage differentiation and function
represents a compelling therapeutic approach, its application to induce immunological tolerance remains
unexplored clinically.
We hypothesize that failure to induce long-term allograft survival may be due, in part, to the lack of therapeutic
protocols that target myeloid cells in vivo. Therefore, the development of an immunotherapy that targets innate
immune cells in vivo and prevents trained immunity represents a promising approach to facilitate long-term
allograft survival. To this aim, we developed high-density lipoprotein (HDL) nanobiologics that target myeloid
cells in vivo and regulate trained immunity by blunting the mTOR pathway. We observed that these mTORi-
HDL nanobiologics prevented aerobic glycolysis and epigenetic modifications underlying inflammatory cytokine
production (signal 3) associated with trained immunity. To enhance therapeutic efficacy, we developed a
second inhibitory CD40-TRAF6 specific nanobiologic CD40i-HDL that prevents co-stimulation (signal 2).
Remarkably, a short-term combined mTORi-HDL and CD40i-HDL nanoimmunotherapy regimen resulted
in indefinite allograft survival with no signs of toxicity or chronic allograft vasculopathy. Having
described that trained immunity can be negatively regulated by HDL nanoparticles to promote tolerance for
transplantation in "naïve" mice, we propose to evaluate the robustness of our combined nanoimmunotherapy in
two settings that compromise the long-term function of the transplanted organ: infection and allosenstization.

## Key facts

- **NIH application ID:** 9920673
- **Project number:** 5R01AI139623-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jordi Ochando
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $572,859
- **Award type:** 5
- **Project period:** 2018-05-25 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920673

## Citation

> US National Institutes of Health, RePORTER application 9920673, Myeloid Specific Targeted Nanoimunotherapy for Organ Transplant Acceptance (5R01AI139623-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9920673. Licensed CC0.

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