# Proteasome targeting for alloreactive plasma cells

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $701,208

## Abstract

Abstract
The induction of plasma cells that secrete antibodies against donor tissue alloantigens is
a major barrier to successful transplantation. Moreover, because many plasma cells are
exceptionally long-lived, the resulting antibody titers are exceptionally durable. Hence
strategies are needed to eliminate long-lived plasma cells that generate allospecific
antibodies. A current dominant strategy for depleting plasma cells centers on
compounds that interfere with the proteasome. Plasma cells are thought to uniquely
require proteasome function to survive. However, for reasons unclear, substantial
numbers of allospecific plasma cells resist the action of available proteasome inhibitors
(PIs). This issue is compounded by the possibility that newly formed plasma cells,
induced by persisting antigens, also contribute substantial amounts of deleterious
antibodies. The chief objective of this project is to establish the impact of PIs on newly
formed versus long-lived plasma cells, and define how biochemical responses to
hypoxia affect mitochondrial apoptosis regulate responses of plasma cells to
proteasome blockade. This work will leverage our unique capacity to resolve and
characterize newly formed versus long-lived plasma cells. Specifically, we will: 1)
Contrast the impact of PIs on newly formed versus long-lived PCs. 2) Test whether
hypoxic niches and HIF1-alpha enhance PC resistance to PIs, and 3) Identify PI-induced
mitochondrial death and resistance mechanisms in long-lived PCs. These studies will
provide unique and needed insights into the mechanisms whereby proteasome inhibition
affects allospecific plasma cell survival and function.

## Key facts

- **NIH application ID:** 10072930
- **Project number:** 1R01AI154932-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** David M Allman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $701,208
- **Award type:** 1
- **Project period:** 2020-07-13 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072930

## Citation

> US National Institutes of Health, RePORTER application 10072930, Proteasome targeting for alloreactive plasma cells (1R01AI154932-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072930. Licensed CC0.

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