# Targeted delivery of immunomodulatory biologics for induction of immune privilege to allogeneic pancreatic islet grafts

> **NIH NIH U01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2021 · $420,968

## Abstract

PROJECT SUMMARY
 Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects ~1% of population worldwide.
Exogenous insulin treatment is the standard of care for T1D, but often negatively affects the quality of life and
is ineffective in preventing recurrent hyperglycemia episodes and chronic complications. Recent studies show
that human islet allografts can restore long-term normoglycemia and insulin independence, protect from severe
hypoglycemia, and slow progression of microvascular lesions in immunosuppressed T1D patients. However,
immune rejection and continuous use of immunosuppression to control rejection are two major limitations
of clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survival
and also has significant adverse effects on the graft and graft recipients. Therefore, the development of novel
approaches to prevent rejection of islet grafts without chronic immunosuppression is a significant goal.
 Allogeneic islets are subject to rejection by both alloreactive and autoreactive T effector (Teff) cells. An
imbalance in the frequency of pathogenic Teff and protective T regulatory (Treg) cells is the underlying cause
of T1D and allogeneic islet graft rejection. Restoring the physiological Teff and Treg balance has significant
therapeutic potential. Approaches attempting to tilt the balance in favor of Treg cells have so far targeted either
Teff or Treg cells individually for modulation with limited success. The primary goal of this application is to
target both cell types simultaneously for modulation for an outcome in favor of Treg cell expansion. This will
be achieved using innovative polyethylene glycol hydrogel particle platforms for graft-targeted delivery
and controlled presentation of two novel biologics serving as agonists of Fas and IL-2R receptors. Teff
cells activated by antigens express Fas receptor and become sensitive to FasL-mediated apoptosis. IL-2R
signaling preferentially sensitizes Teff cells to Fas-induced apoptosis and is also required for Treg cells
(CD4+CD25+FoxP3+) generation, expansion, and survival. Therefore, we hypothesize that the combined use
of agonists of Fas and IL-2R will preferentially eliminate Teff cells and generate/expand Treg cells within
the graft microenvironment, resulting in induced-immune privilege and sustained survival and function of islet
allograft in the absence of any immunosuppression. A set of preliminary data support this hypothesis and
provide strong scientific premise and feasibility for this application. This concept will be tested in three
different allogeneic islet transplantation settings for efficacy and mechanisms; chemically diabetic BALB/c-to-
C57BL/6 mice, spontaneously diabetic C57BL/6-to-NOD mice, and human islets into humanized mice. These
models will generate critical data relevant to the human setting. Furthermore, proof-of-efficacy and the
elucidation of the immune mechanisms regulating effective outcomes ...

## Key facts

- **NIH application ID:** 10227259
- **Project number:** 5U01AI132817-05
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Andres J Garcia
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $420,968
- **Award type:** 5
- **Project period:** 2020-05-12 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10227259

## Citation

> US National Institutes of Health, RePORTER application 10227259, Targeted delivery of immunomodulatory biologics for induction of immune privilege to allogeneic pancreatic islet grafts (5U01AI132817-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10227259. Licensed CC0.

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