# Graft extracellular vesicles as promoters of anti-donor immunity in cardiac and skin transplantation

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $655,927

## Abstract

SUMMARY
The innate and adaptive immune response against allografts is the main impediment to successful transplantation.
Heart transplantation is the best option for selected pediatric and adult patients with end-stage heart failure,
however, the threat of rejection remains high, despite improvements in immunosuppressive therapies, conditioning
regimens and medical care. Importantly, currently used interventions are not donor-specific and therefore may
cause increased risk of infections and cancer. A deeper understanding of the basis of allo-recognition is needed
for the development of novel donor-specific therapies to treat graft rejection minimizing the harmful side effects.
 Recent studies have challenged the dogma that initiation or re-activation of anti-donor immunity in graft-
draining secondary lymphoid tissues (SLTs) depends mainly on donor Ag-presenting cells (APCs) mobilized from
the grafts. Increasing evidence and our preliminary studies indicate that heart and non-vascularized skin allografts
release extracellular vesicles (EVs) carrying donor-Ag that traffic to the SLTs where the graft EVs stimulate donor-
reactive B cells and T cells. Despite increasing information during the past 5 years on the role of graft EVs on
elicitation of anti-donor immunity and their potential use as biomarkers in transplantation, the mechanisms in vivo
by which graft EVs interact with recipient’s immune cells in graft-draining SLTs and promote anti-donor immunity
remain largely unknown.
 The family of EVs encompasses vesicles with different biogenesis, size and composition that includes
exosomes and microvesicles. Although growing evidence indicates that EVs represent a mechanism by which
cells horizontally transfer proteins, mRNAs, non-coding RNAs and lipids, the function of EVs in vivo remains an
enigma. Therefore, we propose to investigate the mechanisms in vivo by which graft EVs initiate or re-activate
in graft-draining SLTs, the innate and adaptive immune responses that lead to rejection of allografts. We will
analyze these mechanisms in mouse experimental models of cardiac and non-vascularized skin allografts.
 We hypothesize that “graft EVs constitute a cell-free platform that by multiple mechanisms initiates
or re-activates the anti-donor immune response in the recipient’s SLTs”. This application will investigate
these mechanisms in situ and in vivo using transplant models in mice and a translational model in humanized
mice. We will test our hypothesis in the following aims: Aim 1 will investigate the origin of graft EVs and their
effects on recipient APCs in graft-draining SLTs, Aim 2 will analyze the mechanisms by which graft EVs generate
anti-donor B cell immunity in SLTs and Aim 3 will analyze how graft EVs elicit anti-donor T cell immunity in SLTs
and its relevance to transplantation in humans. Our long-term goal is to understand how graft EVs function in
vivo to provide new grounds for development of EV-based therapies and disease markers o...

## Key facts

- **NIH application ID:** 10560271
- **Project number:** 1R01AI174273-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Adrian E. Morelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $655,927
- **Award type:** 1
- **Project period:** 2022-09-19 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10560271

## Citation

> US National Institutes of Health, RePORTER application 10560271, Graft extracellular vesicles as promoters of anti-donor immunity in cardiac and skin transplantation (1R01AI174273-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10560271. Licensed CC0.

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