# Exosome-mediated Tolerance in combined Kidney and Stem Cell Transplantation

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $193,802

## Abstract

Abstract
With the advent of mixed chimerism as a clinical transplantation tolerance strategy, understanding the
mechanisms leading to stable tolerance has become critical. We now have evidence that a key component of
transplant tolerance is provided by tiny, virus-sized particles called exosomes. Exosomes derived from Treg
cells were not only critical to the mechanism of donor-specific transfusion (DST) co-stimulation (CoS)
blockade-induced tolerance, but they may also be the basis of tolerance effects resulting from bi-directional
regulation between host and living-related kidney donor . Besides Treg-derived exosomes, the recent
discovery of a major role for exosomes from donor “passenger” DC (dendritic cells) in transplant rejection led
us to test the hypothesis that DC exosomes could also do the opposite, i.e. promote transplant tolerance. We
found that maternal DC microchimerism, resulting from the interaction of mother and child in utero and
persisting in the neonate and throughout adult life, produce exosomes that amplify the tolerogenic impact of
rare allogeneic cells. This discovery could finally explain the higher probability of graft survival in a transplant
between siblings that differ for HLA at the non-inherited maternal haplotype. We propose, herein, a pilot
immune monitoring study of: 1) normal HLA-identical and 1 haplotype mismatch living related donor (LRD)
kidney transplants, and 2) the same patient-donor types, but enrolled in a combined total lymphoid irradiation
(TLI)+ kidney/hematopoetic stem cell (HSC) transplantation trial at the UW-Madison. The goal of the trial
would be to determine if monitoring of Treg- and DC-derived exosomes will predict which patients are
successful, and which will fail to achieve tolerance. We hypothesize that in living-related donor-recipient
pairs with pre-transplant “bi-directional regulation”, host and graft-resident Tregs will produce
exosomes that cross-dressed bystander T & B cells with IL35, promoting infectious tolerance.
Similarly, we hypothesize that DC exosomes capable of inducing PD-L1 expression in HLA-cross-
dressed (XD) DC will correlate with excellent graft outcome. We predict that both of these positive
exosome effects will be amplified in the context of RTx/TLI/HSC pre-conditioning. Failure to detect IL35 on LC
exosomes, and PD-L1 miRs/lncRNAs within DC exosomes in successful tolerance induction will support a
“null” hypothesis. Our goal is to discover the role of Treg- and DC-derived exosomes in a clinical tolerance
trial.

## Key facts

- **NIH application ID:** 9987510
- **Project number:** 5R21AI147157-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** david Paul foley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,802
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987510

## Citation

> US National Institutes of Health, RePORTER application 9987510, Exosome-mediated Tolerance in combined Kidney and Stem Cell Transplantation (5R21AI147157-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9987510. Licensed CC0.

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