# TARGETING HUMAN PLASMA CELLS TO OVERCOME HUMORAL RESPONSES IN TRANSPLANTATION

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $486,612

## Abstract

PROJECT SUMMARY:
Our overarching programmatic goal is to implement rationally-designed therapeutic strategies to improve
transplantation rates and reduce allograft loss by reducing or eliminating HLA antibodies (Abs). Patients who
have developed HLA Abs as a result of a previous transplant, pregnancy, or blood transfusion may undergo
excessive waiting times prior to transplantation because a compatible donor cannot be found. Recent FDA
Workshops have been conducted because traditional antihumoral therapies with intravenous immunoglobulin
(IVIg) and plasmapheresis do not provide acceptable outcomes for rejection treatment or removal of HLA Abs
prior to transplantation (termed desensitization). Our prior studies indicate that bone marrow plasma cells
(BMPCs) are the major source of HLA Ab production. BMPCs remain inadequately characterized and exhibit
substantial resistance to current therapies in vivo. Several desensitization strategies, e.g., plasmapheresis,
steroids, IVIg and rituximab to deplete CD20+ B cells, have been investigated to eradicate Ab-producing PCs,
remove preformed anti-HLA Abs or reverse acute Ab-mediated rejection (AMR) with limited success. A plausible
explanation for the shortcomings of these strategies is that they do not deplete BMPCs. To achieve our mission
and overcome these obstacles, we propose PC targeted therapies as a therapeutic approach that can be
enhanced by conducting appropriate basic science studies with subsequent evaluation in preclinical models. In
this Project, we will focus on proteasome inhibitor (PI) therapy as the cornerstone of current PC targeted
therapies. In Aim 1, we will employ active site-specific inhibitors and covalent probes to quantitate structural and
functional adaptations in proteasomes from the BMPCs of HLA-sensitized patients after in vivo PI therapy. Our
prior studies indicate that immunoproteasomes, a highly specialized proteasomal variant, are upregulated in
BMPCs resistant to standard PI therapy. Importantly, immunoproteasome-specific inhibitors target BMPCs that
are resistant to standard PI therapy. In Aim 2, we will employ a novel ex vivo platform that extends the longevity
of patient BMPCs through co-culture with BM stromal cell media. We will integrate the results to reveal rationally-
designed drug cocktails that synergistically target drug-resistant BMPCs from human patients and that lack broad
off-target toxicities. In Aim 3, we will we will deploy cutting-edge genomic and bioinformatic tools to better define
the cellular and genetic heterogeneity of BMPCs. Single cell (sc)RNA-Seq transcriptomic profiling will be
performed to identify key genomic variations and signatures that define BMPC heterogeneity, reveal rare cell
populations and determine the effect of HLA-sensitization and PI therapy on BMPC subsets. Taken together, the
results will create tools that can be generalized to improve antihumoral therapies for kidney, heart and liver
transplant. Our highly organized, integ...

## Key facts

- **NIH application ID:** 10206455
- **Project number:** 7R01AI139141-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** James Joseph Driscoll
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $486,612
- **Award type:** 7
- **Project period:** 2018-12-17 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206455

## Citation

> US National Institutes of Health, RePORTER application 10206455, TARGETING HUMAN PLASMA CELLS TO OVERCOME HUMORAL RESPONSES IN TRANSPLANTATION (7R01AI139141-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10206455. Licensed CC0.

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