# Immunosuppression-free islet transplantation via localized immunomodulatory exosome tethering

> **NIH NIH R21** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2023 · $223,270

## Abstract

PROJECT SUMMARY/ABSTRACT
 Clinical islet transplantation is a promising treatment for insulin-dependent diabetic patients, with the
potential to eliminate long-term secondary complications by restoring native insulin signaling. While clinical
successes have demonstrated the feasibility of achieving insulin independence through islet replacement
therapy, the necessity of a long-term immunosuppressive regimen limits the widespread applicability of this
procedure, as the substantial risk associated with chronic immunosuppression outweighs the risk of diabetes
associated morbidities. As a result, there is great interest in the development of macroencapsulation devices to
isolate transplanted cells from the recipient immune system, with the intent to eliminate immune recognition via
the direct antigen presentation pathway. While this strategy can reduce immune response to the graft,
encapsulation cannot prevent the diffusion of shed antigens, which activate immune cells via the indirect antigen
presentation pathway to ultimately target and destroy the transplanted cells. As such, a synergistic approach to
macroencapsulation is required to fully ameliorate the immune response to islet grafts.
 The placental microenvironment is a unique biological example of localized, normal physiological
tolerance, maintained by trophoblasts at the fetal-maternal interface via two mechanisms: (1) creating a barrier
to prevent contact between allogeneic tissue and host, and (2) localized presentation and secretion of
immunomodulatory factors to induce tolerogenic innate and adaptive immune cells. One potent method by which
trophoblasts deliver immunomodulatory payloads is via secreted exosomes. We aim to mimic these two
mechanisms of trophoblast-mediated tolerance through encapsulating islets in an immunoisolating hydrogel
device and tethering immunomodulatory trophoblast-derived exosomes to the device surface.
 We hypothesize that localized presentation of immunomodulatory trophoblast-derived exosomes at the
surface of a synthetic hydrogel macroencapsulation device will synergize with immunoisolation to produce
localized immune tolerance to the graft. We anticipate that localized exosome presentation will result in local
tolerance to the graft by inducing tolerogenic innate and adaptive immune cells at the site of transplantation.
Encapsulation within the hydrogel device will prevent direct antigen presentation, and surface-bound exosomes
will induce tolerogenic antigen presenting cells, preventing immune destruction via indirect antigen recognition.
These hypotheses will be addressed in the experiments of the following Specific Aims: (1) Engineer an
immunomodulating exosome-presenting synthetic hydrogel-based macroencapsulation device; and (2) Evaluate
immunomodulatory macroencapsulation device impact on the localized graft immune environment. We
anticipate that this study will demonstrate the immunosuppressive capacity of tolerogenic trophoblast exosomes,
and their ...

## Key facts

- **NIH application ID:** 10610867
- **Project number:** 5R21AI151865-02
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** Jessica Diane Weaver
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $223,270
- **Award type:** 5
- **Project period:** 2022-04-19 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10610867

## Citation

> US National Institutes of Health, RePORTER application 10610867, Immunosuppression-free islet transplantation via localized immunomodulatory exosome tethering (5R21AI151865-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10610867. Licensed CC0.

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