# Mechanisms of B cell-Dependent Transplantation Tolerance

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $508,916

## Abstract

PROJECT SUMMARY / ABSTRACT
B cells have long been regarded as having the primary duties of promoting immunity by presenting antigen to T
cells and producing antibody. More recently it has been appreciated that, similar to the T cell arm of the
adaptive immune response, the B cell arm is charged with significant regulatory responsibility. This was first
appreciated in experimental autoimmunity models in which the absence of B cells exacerbated disease. In the
transplant arena, we first demonstrated a model of transplant tolerance (based on anti-CD45RB antibody
therapy) that was dependent on the presence of B cells. Since this finding, a number of investigators have
substantiated the generality of this property, showing a similar B cell requirement using other tolerogenic
regimens including co-stimulation blockade, anti-TIM-1, and anti-TIM-4, and we recently reported the
combination of anti-CD45RB and anti-TIM-1 to behave similarly in more stringent strain combinations. These
models provide opportunity to delineate the mechanism of action of Bregs, to examine their role in rejection
and tolerance, and to begin to explore their potential as a cellular therapeutic.
During the last funding period we made significant progress in defining the in vivo action of Bregs. Some of the
key findings that set the stage for the current proposal include that tolerance induced by anti-CD45RB and anti-
TIM-1 treatment is B cell dependent and can be adoptively transferred from tolerant hosts to both B cell
deficient and immunologically replete untreated mice. We were also the first to report that antibody induced
tolerance and adoptive transfer of Breg tolerance is dependent on host Tregs. In addition, we recently
determined that in our tolerance model, TGF-β is required for development of tolerance and, specifically, that B
cell secretion of TGF-β is essential. This provides a natural link between Bregs and Tregs and will be dissected
further in the proposed studies of Aim I. We recently initiate studies of naïve B cells activated by TLR ligands
that also exhibit graft survival prolonging regulatory properties. In Aim II, compare the mechanism of action of
these cells with those recovered from tolerance hosts. Finally, in Aim III, we begin to explore the potential of in
vitro expanded Bregs (eBregs) both to facilitate our mechanistic analyses and to begin to assess the
translational potential of Bregs as a means to control alloimmunity and autoimmunity.

## Key facts

- **NIH application ID:** 10062841
- **Project number:** 5R01AI057851-15
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JAMES FRANCIS MARKMANN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,916
- **Award type:** 5
- **Project period:** 2006-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062841

## Citation

> US National Institutes of Health, RePORTER application 10062841, Mechanisms of B cell-Dependent Transplantation Tolerance (5R01AI057851-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10062841. Licensed CC0.

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