# Leveraging humoral immunity to promote commensal microbial protection from T1D

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $264,000

## Abstract

PROJECT SUMMARY
Type 1 diabetes (T1D) is an autoimmune disease that affects millions of people worldwide. The incidence of
T1D is rising, especially in young children. Although significant progress has been made to predict who is at
risk for developing T1D, there are no effective therapies to prevent this disease. Both genetic and
environmental factors contribute to the risk of developing T1D. Certain human leukocyte antigen (HLA)
haplotypes dominantly protect against the development of T1D, yet the mechanism of this remarkable
protection from autoimmunity is not well-understood. NOD mice, the most widely used model of T1D, do not
express a major histocompatibility complex (MHC) class II E molecule. Transgenic expression of the MHCII E
molecule in NOD mice (Eα16/NOD) completely prevents T1D, mirroring dominant HLA protection from T1D in
humans. Using these Eα16/NOD mice as a model of dominant genetic protection from T1D, we recently
demonstrated that MHC/HLA genetic protection from autoimmunity operates via immune system selection of
diabetes-protective commensal microbiota early in life, which in turn, influences the developing immune
system. Since we find an increased proportion of intestinal Tregs and a distinct early-life microbiome in
Ea16/NOD mice, our central hypothesis is that specific microbes prevent T1D by promoting
development of diabetes-protective CD4+ regulatory T cells (Tregs). Modeling of HLA class II dominant
protection from T1D in murine models may provide critical insights to support our long-term goal of developing
microbiota-based therapies to prevent T1D in humans. Due to the complexity and high levels of variability of
the intestinal microbiome, determining the specific microbial strains that educate the immune system is
problematic. Building upon established techniques of microbial flow cytometry of antibody-coated commensal
microbes, we developed an innovative approach called mFLOW-SEQ to identify microbes that stimulate the
CD4+ T cell compartment in a model of genetic protection from T1D. Aim 1 leverages our innovative mFLOW-
SEQ approach to identify commensal microbes that induce CD4+ Treg cells and prevent T1D. Aim 2 uses
genetic models to determine the extent to which early-life Treg cells prevent autoimmunity in genetically
protected Eα16/NOD mice. Successful completion of these aims will provide critical information on which early-
life microbes impact the development of the immune system to prevent T1D and further whether early-life Tregs
provide protection from T1D. In addition, mFLOW-SEQ is an innovative tool for identifying microbes that
modulate the immune system in mice. As a future direction, we envision applying mFLOW-SEQ to human
samples to help generate personalized microbiota therapies based on HLA haplotypes for human patients at
risk for T1D.

## Key facts

- **NIH application ID:** 10042330
- **Project number:** 1R21AI153956-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Michael A Silverman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $264,000
- **Award type:** 1
- **Project period:** 2020-06-17 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10042330

## Citation

> US National Institutes of Health, RePORTER application 10042330, Leveraging humoral immunity to promote commensal microbial protection from T1D (1R21AI153956-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10042330. Licensed CC0.

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