# Basic and Translational Mechanisms of Alloimmunization to RBC Transfusion

> **NIH NIH P01** · UNIVERSITY OF VIRGINIA · 2024 · $2,286,537

## Abstract

Alloimmunization to transfused RBCs remains a major problem for the large number of patients who require
transfusion (approximately 1 out of 70 people (~5,000,000 patients) annually in the USA alone). Although a
barrier to transfusion in multiple settings, alloimmunization is particularly problematic for patients with sickle cell
disease (SCD) due to 1) the increased rate of alloimmunization (up to 30%), 2) the need for chronic transfusion,
and 3) the risk of undetected (or new) alloantibodies causing potentially catastrophic hyperhemolysis. There are
very few effective therapeutic interventions to prevent RBC alloimmunization (e.g., extensive antigen matching).
For all transfusion indications, patients tend to be either “responders” that develop alloantibodies over time with
ongoing transfusion or “non-responders” with no detectable alloantibodies even after many transfusions.
Currently, we cannot predict which patients are likely to be responders and become alloimmunized. This P01
focuses on addressing the persistent problem of RBC alloimmunization for the large number of patients who
require transfusions and are at risk for alloimmunization. The program is structured around a central core (Core
A) that will collect longitudinal samples from a cohort of 2000 patients with SCD (at steady state, at time of
transfusion, and one-month post-transfusion) linked to detailed clinical information, including RBC
alloimmunization. Projects 1-3 combine novel translational murine models with clinical samples from Core A
while Project 4 uses samples from Core A to test hypotheses through an omics-based approach and generates
data on pathways studied in Projects 1-3. In this way, the proposed program creates a synergy of approaches
with the ability to translate murine findings into humans and model human findings in mice. Using the samples
from Core A as a common resource, four projects are proposed. Project 1 builds on a novel observation that
a mouse model of SLE recapitulates increased RBC alloimmunization observed in humans with SLE and utilizes
the model and samples from Core A to test the mechanistic role of TLR7, TLR9 and anti-nucleic acid antibodies
in RBC alloimmunization. Project 2 builds on our novel observation that multiple purinergic signaling pathways
regulate RBC alloimmunization in mice and utilizes mouse models and samples form Core A to test the
mechanistic role of CD73, AMP, Adora1, adenosine and Adora2b in RBC alloimmunization. Project 3 proposes
mechanistically driven studies in pre-clinical models and human studies to expand upon our novel finding that
reticulocytes (in donor RBC units or in transfusion recipients) are a risk factor for RBC alloimmunization. Project
4 will investigate the underlying genetic risk factors that predispose a given patient with SCD through analysis of
whole genome sequencing and the specific molecular drivers of alloimmunization to a given transfusion through
analysis of single cell RNASeq data. This P01 is ...

## Key facts

- **NIH application ID:** 11070282
- **Project number:** 5P01HL169552-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** JAMES C. ZIMRING
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,286,537
- **Award type:** 5
- **Project period:** 2023-09-10 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11070282

## Citation

> US National Institutes of Health, RePORTER application 11070282, Basic and Translational Mechanisms of Alloimmunization to RBC Transfusion (5P01HL169552-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11070282. Licensed CC0.

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