# Human B cell infiltration into allografts: mechanisms and molecules

> **NIH NIH R21** · YALE UNIVERSITY · 2021 · $209,375

## Abstract

7. PROJECT SUMMARY/ABSTRACT
Rates of late renal allograft loss due to chronic rejection have not significantly changed over the past three
decades despite marked improvements in controlling acute rejection. While the immune pathogenesis is
incompletely understood, a significant proportion of allografts contain infiltrated host B cells and the presence
of B cells correlates with poor prognosis that may be independent of the presence of a donor specific antibody.
While T cell recruitment to allografts is well understood and may be initiated by either chemokines or antigen
presentation within the vascular lumen, much less is known about B cell recruitment. We propose to study
these processes with the goal of identifying pathways and molecular targets that may inhibit B cell infiltration of
grafts. To study if and how this process can be induced by chemokines, we will employ both high dimensional
cyclic tissue immunofluorescence microscopy of human allograft tissue and in vitro assays of transendothelial
migration (TEM) by human peripheral blood B cells. Tissue analyses will provide information re the subtypes of
B cells found within graft infiltrates, the chemokine and adhesion receptors they express, and their proximity to
activated endothelial cells that are the likely point of entry. In vitro assays will use human microvascular
endothelial cell monolayers in microfluidic chambers to characterize and manipulate B cells capable of
undergoing TEM using approaches we developed in our T cell studies. To study if and how this process can be
induced by antigen, we will use our high dimensional IF approach to determine if B cells within the graft are
interacting with relevant T cell populations and we will use laser capture microscopy to isolate individual B cells
from which we will clone and express the antigen combining regions to generate antibodies and then test
specificity for different types of graft antigens. We will also modify our in vitro TEM assays to allow endothelial
cells to cross-link and signal through the B cell receptor for antigen by display of anti-human kappa antibody,
again employing a technique we used to mimic T cell receptor signaling with anti-human CD3. We anticipate
that these studies will lead to identification of targets, possibly inhibitable by currently approved agents, that
can limit B cell recruitment into allografts, an intervention that may reduce late graft loss without the risk to
immunosuppressed patients mediated by total B cell ablation.

## Key facts

- **NIH application ID:** 10169253
- **Project number:** 5R21AI154187-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Thomas David Manes
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2020-05-21 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169253

## Citation

> US National Institutes of Health, RePORTER application 10169253, Human B cell infiltration into allografts: mechanisms and molecules (5R21AI154187-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10169253. Licensed CC0.

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