# Deconstructing B cell transplantation tolerance

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $549,342

## Abstract

Summary/Abstract
Transplantation tolerance, a state in which immunosuppression can be stopped while grafts remain functional,
is a major goal in clinical transplantation field as it promises to reduce side effects, costs and non-adherence
consequences associated with the current need for life-long immunosuppression. Tolerance can be
spontaneously achieved in rare recipients of kidney allografts and more frequently in liver transplant recipients.
In some cases tolerance is stable, while in others the allografts eventually fail. Emerging data have led us to
hypothesize that robust peripherally induced transplantation tolerance depends on multiple redundant cell-
intrinsic and -extrinsic mechanisms to control alloreactive T and B cells. This proposal focuses of defining the
mechanisms that control alloreactive B cells. This focus is based on considerable experimental and clinical
data that donor-specific antibody (DSA) is an independent barrier to long-term graft acceptance, and clinical
observation that the development of antibodies in tolerant patients leads ultimately to allograft rejection. Over
the past few years, my laboratory has focused on tracing the fate of endogenous alloreactive B cells in
transplantation rejection and tolerance. Here, we propose to build on our exciting preliminary observations
made in a mouse model of cardiac allograft tolerance that donor-specific B cells are not completely deleted but
acquire a cell-autonomous dysfunctional state that prevents their differentiation into antibody-secreting cells
and that is resistant to T cell help. However, these tolerant cells are not completely inert and, remarkably, are
able to suppress naïve B cells in a donor-specific manner. We propose to define the: Aim 1. in vivo cellular
requirements for donor-reactive B cells to become intrinsically tolerant; Aim 2. mechanisms maintaining donor-
specific B cell-intrinsic tolerance and preventing their development into antibody-secreting cells; Aim 3.
Mechanisms and consequences of tolerant B cell-mediated suppression. We anticipate that the completion of
these studies will provide insights into novel mechanisms that result in and maintain B cell tolerance,
biomarkers that distinguish tolerant B cells from naïve or effector/memory B cells, and potential therapeutic
targets for controlling allograft-specific antibody responses in transplant recipients.

## Key facts

- **NIH application ID:** 10216969
- **Project number:** 5R01AI142747-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Anita S Chong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $549,342
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216969

## Citation

> US National Institutes of Health, RePORTER application 10216969, Deconstructing B cell transplantation tolerance (5R01AI142747-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10216969. Licensed CC0.

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