# Tissue-engineered lymph node stroma to study peripheral tolerance in autoimmune diabetes

> **NIH NIH R56** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $432,804

## Abstract

Project Summary:
Type-1 diabetes (T1D) is caused by autoreactive T cells that selectively destroy insulin-secreting b cells in the
pancreas. Loss of immunological tolerance to b cells causes T1D, but the underlying mechanisms are poorly
understood, preventing the development of a cure for T1D. A major component of peripheral tolerance to prevent
T1D is the regulation of circulating autoreactive T cells in lymph nodes (LNs) by interactions with tolerogenic Ag-
presenting cells (APCs) and regulatory T cells, both of which appear to be defective in T1D.
Fibroblastic reticular cells (FRCs) form the LN reticula that guide migration and interactions of T cells and APCs.
FRCs are also responsible for remodeling the LN and allowing its expansion during inflammation. Relevant to
autoimmune diseases, FRCs are non-professional APCs that can induce antigen-specific tolerance by
expressing and presenting antigens to specific T cells without co-stimulatory signals, leading to T cell
engagement (stimulation and proliferation) followed by deletion.
Most studies have been done using transgenic mice for overexpression of artificial (not disease relevant)
antigens in FRCs; thus, the role of FRCs in maintaining peripheral tolerance to disease-relevant self-antigens is
poorly understood. We found that in T1D, relative frequency, antigen expression levels and reticular organization
of LN FRCs are affected. One goal of this proposal is to use innovative tissue-engineered FRC reticula that
recapitulate FRC reticular organization in the LN paracortex and T1D known self-antigen expression to study
how FRC reticular properties (aim 1.1) and antigens expression levels (aim 2.1) affect T cell engagement in vitro
through co-culture studies.
While professional APCs can switch to immunogenic phenotypes and promote T1D, non-professional APCs like
FRCs are less likely to do so. We showed that promoting formation of FRC reticula expressing T1D antigens is
sufficient to induce tolerance and prevent T1D in non-obese diabetic (NOD) mice. Thus, a second goal of this
proposal is to test in NOD mice whether we can delete autoreactive T cells from the systemic circulation to
ameliorate T1D by (i) attracting them to implanted engineered reticula and by (ii) promoting tolerogenic T cell
engagement by modulating FRC reticular properties (aim 1.2) and/or FRC antigen-expression levels (aim 2.2).

## Key facts

- **NIH application ID:** 10299866
- **Project number:** 1R56AI151217-01A1
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Alice Tomei
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,804
- **Award type:** 1
- **Project period:** 2020-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10299866

## Citation

> US National Institutes of Health, RePORTER application 10299866, Tissue-engineered lymph node stroma to study peripheral tolerance in autoimmune diabetes (1R56AI151217-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10299866. Licensed CC0.

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