# Intrarenal B cells in acute kidney allograft rejection

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $791,315

## Abstract

ABSTRACT
 In a seminal paper, Sarwal et al.1 reported that the presence of a B cell gene signature and dense clusters
of B cells in the renal biopsies was strongly associated with glucocorticoid-resistant T cell-mediated graft
rejection (TCMR) and kidney allograft loss. They proposed a hypothesis that, despite standard of care
immunosuppression, infiltrating B cells play a pivotal role in a subset of acute cellular rejection of kidney
allografts in the clinic. While some subsequent studies supported this hypothesis, others reported opposite
outcomes. As a result, the role of intrarenal B cells in clinical TCMR is currently unclear, and an understanding
of their role is urgently required to allow clinicians to rationally decide if B cell depletion might be useful for
reversing steroid-resistant TCMR. We hypothesize that the identification of additional features of intrarenal B
cells or of the rejecting biopsy are required to more accurately predict poor graft outcome and the need for B
cell depletion to treat TCMR. These features include an understanding the specificity of intrarenal B cells and
their functional properties, as well as the inflammation architecture of the biopsy. To this end, we have
developed two innovative approaches to understand in situ adaptive T and B cell immunity in human biopsies
from rejecting kidney allografts. First, we are able to pair the transcriptional state in single B cells with the
antigenic specificity of the antibody they secrete. Sorted B cells from renal biopsies are subjected to single cell
(sc) RNA-Seq, and the immunoglobulin variable regions are cloned from these same cells and expressed
corresponding antibodies. Second, we have developed a novel approach to characterize the spatial
architecture between different immune cell populations in human tissue and identify functional relationships2,3.
Using a novel deep convolutional neural network (DCNN), coupled to a tuned neural network (TNN), we can
accurately capture T cell shape change upon recognition of antigen presented by dendritic cells (DCs) in
multicolor confocal micrographs. Therefore, this analytic pipeline (Cell Distance Mapping, CDM) can identify
and quantify antigen presentation in fixed tissue samples from both mice and humans. We will use CDM to
study T cell interactions with B cells or dendritic cells (DCs) in rejecting kidney biopsies. Third, we developed a
mouse model of kidney transplantation to address mechanistic questions raised by observations made from
the human renal biopsies. We will apply these three approaches to test our project hypothesis in two Aims:
 Aim 1. Test the hypothesis that the different transcriptional and functional states of intrarenal B cells during
rejection are associated with B cell receptor (BCR) specificity and rejection type.
 Aim 2: Test the hypothesis that the type of cellular rejection (T cell mediated rejection vs. mixed T cell- and
antibody-mediated rejection) is defined by characteristic in situ cellular...

## Key facts

- **NIH application ID:** 10106571
- **Project number:** 5R01AI148705-02
- **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:** $791,315
- **Award type:** 5
- **Project period:** 2020-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106571

## Citation

> US National Institutes of Health, RePORTER application 10106571, Intrarenal B cells in acute kidney allograft rejection (5R01AI148705-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10106571. Licensed CC0.

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