# Disruption of Treg-dependent Tolerance by B lymphocytes in Islet Transplantation

> **NIH NIH R56** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $173,000

## Abstract

Project Summary
Although clinical approaches directed at T cells, B cells, and immune effector molecules prevent transplant
rejection and slow the progression of autoimmune disease, these therapies do not induce durable immune
tolerance as immune-mediated destruction recurs when therapy is stopped. This failure is due to an imbalance
in regulatory and effector immunity that no current approach has been able to address and is particularly
difficult in approaches like islet transplantation for T1D where the induction of durable immune tolerance
would be curative alongside islet replacement. Islet loss following transplant and autoimmune attack in T1D
are both heralded by the presence of anti-islet antibodies, which are so important in signifying incipient islet
injury that they define new onset stage 1 T1D. Traditionally, it has been thought that the production of these
antibodies is a sign of T-B collaboration that leads to effector cell activation. This proposal will investigate an
alternative hypothesis that B lymphocytes also directly erode immune regulatory cell function. In the absence
of B lymphocytes, we find that the T1D-prone NOD immune system becomes susceptible to inducible
transplantation tolerance, which is not otherwise achievable in this background, and that tolerance following
islet transplantation is also enhanced in healthy, non-autoimmune recipients. This successful transplantation
was not due to loss of effector cell specificities in the absence of B cells but instead was associated with an
increase in islet-protective Tregs and a recovery in their response to immune therapy. Thus, we have
determined that B lymphocytes are the critical barrier to successful immune reprogramming and that they act
by disrupting Treg function. We hypothesize that B cells interact with T cells during their development through
both antigen-specific (signal 1) and co-stimulatory (signal 2) interactions to shape the balance of Tregs and
Teffs in a way that depends on B cell tolerance. In this proposal, we will investigate this new paradigm in two
aims. In Aim 1, we will determine the role of antigen presentation, acquisition, and tissue origin on the
interaction of B lymphocytes and Tregs using transgenic systems to control and trace their relationships. In
Aim 2, we will determine the mechanism of deleterious B cell-Treg contact including the roles of B cell
development, B cell tolerance including anergy, and the intercellular interactions between B and T cells that
modulate immunity. Together, these aims will reveal how B cells impede tolerance induction and how this
barrier may be repaired to permit inducible immune tolerance in islet transplantation.

## Key facts

- **NIH application ID:** 10347665
- **Project number:** 1R56DK128337-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Daniel J. Moore
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $173,000
- **Award type:** 1
- **Project period:** 2021-04-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347665

## Citation

> US National Institutes of Health, RePORTER application 10347665, Disruption of Treg-dependent Tolerance by B lymphocytes in Islet Transplantation (1R56DK128337-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10347665. Licensed CC0.

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