# Exosomes and Donor Antigen Cross-dressing in Pancreatic Islet Transplantation

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $454,391

## Abstract

PROJECT SUMMARY / ABSTRACT
The ultimate goal of islet transplantation is to achieve tolerance defined as long-tem engraftment without
maintenance immunosuppression. Several studies suggest that certain extracellular vesicles (exosomes) play
an essential role in the immune responses involved in both rejection and tolerance of allogeneic transplants.
Recently, we reported that, after pancreatic islet transplantation in mice, many recipient cells, take up donor
vesicles and present allogeneic MHC molecules on their surface (allo-MHC cross-dressing); a process leading
to activation of alloreactive T cells in vivo. In addition, exosomes released by pancreatic insulin-secreting beta
cells are known to promote inflammation and diabetes through transfer of auto-antigens and RNA.
Altogether, this suggests that exosomes might play a key role in the rejection of islet allografts. Supporting this
view, we have obtained preliminary evidence that in vivo blocking of donor exosome production with 2 agents,
GW4869 and cambinol, inhibited allo-MHC cross-dressing and prolonged survival of heart allografts in mice
(up to 80 days). Most relevant to this proposal, we have obtained preliminary data showing that treatment of
allogeneic islets in vitro (pre-injection) with these GW4869 suppressed donor MHC cross-dressing and nearly
abrogated activation of alloreactive T cells in mice recipient of these islets.
Contrasting with their role in rejection, exosomes have also been shown to promote immune tolerance. For
instance, exosomes derived from FoxP3+ regulatory T cells (Treg-exosomes) suppress inflammation and can
mediate immune tolerance of auto- and allo-antigens in rodents. On the other hand, to our knowledge, the
tolerogenicity of exosomes produced by regulatory B cells (Breg-exosomes) has never been investigated.
Our objectives are: 1) to investigate the nature of the cells and antigens involved in donor exosome release
and cross-dressing after islet transplantation and, 2) test whether long-term islet allograft survival could be
achieved through inhibition of donor exosome production and/or MHC cross-dressing or via recipient
administration with tolerogenic exosomes.
Aim 1. Investigate the mechanisms involved in donor antigen cross-dressing of recipient cells after
islet transplantation
Aim 2. Inhibit donor exosome release and cross-dressing in islet-transplanted mice
Aim 3. Achieve long-term islet allograft survival using exosomes derived from regulatory cells
We anticipate that our proposal will 1) bring new insights into the mechanisms underlying the initiation of
alloimmunity and rejection process after pancreatic islet transplantation and, 2) set the path for the design of
novel exosome-based tolerance protocols in islet transplantation and potentially autoimmune and other
inflammatory immunological disorders.

## Key facts

- **NIH application ID:** 9834884
- **Project number:** 5R01DK115618-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** GILLES A BENICHOU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,391
- **Award type:** 5
- **Project period:** 2017-12-06 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834884

## Citation

> US National Institutes of Health, RePORTER application 9834884, Exosomes and Donor Antigen Cross-dressing in Pancreatic Islet Transplantation (5R01DK115618-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9834884. Licensed CC0.

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