# Basic and Translational Mechanisms of Alloimmunization to RBC Transfusion.  Project 4

> **NIH NIH P01** · UNIVERSITY OF VIRGINIA · 2024 · $458,329

## Abstract

Project Summary/Abstract
Individuals with sickle cell disease (SCD) have a significantly higher red blood cell (RBC) alloimmunization rate
than other populations receiving transfused donor RBCs. Depending on the study, circumstances of transfusion,
and environment, it has been reported that 18-47% of individuals with SCD become immunized to RBC allo-
antigens following a transfusion and are also more likely to then make additional alloantibodies with subsequent
transfusions. Transfusions in the setting of an acute SCD complication have an 8-12-fold higher odds ratio(1) of
resulting in alloantibody formation compared to those given at steady-state. We hypothesize that we will identify
key drivers of alloimmunization with a large-scale, unbiased human study that integrates recipient omics and
environmental conditions (i.e., presence or absence of acute illness and high levels of inflammation) at the time
of transfusion. We will test this through first identifying variants associated with alloimmunization through analysis
of genome sequencing (WGS) from responders and non-responders. We hypothesize that SCD individuals with
African heritage will have genetic variants associated with increased immunogenicity. To test this, we will
analyze the WGS of our Emory SCD cohort (n=2000) who have or have not developed alloantibodies after 10
or more blood transfusions and compare to WGS from the REDSIII cohort in TOPMed, which has
alloimmunization phenotypes on 2800 subjects with SCD from Brazil. Then, we will assess transcriptome
changes of leukocyte subsets at baseline, at time of transfusion, and at one-month post-transfusion in individuals
with SCD who did or did not develop alloimmunization. We hypothesize that we will identify alterations in gene
expression (and affiliated pathways) that associate with alloimmunization. This will have the immediate benefit
of allowing us to develop a transcriptional risk score (TRS) for alloimmunization, and the longer-term benefit if
identifying pathways for rational development of therapeutic interventions. Finally, we will assess the impact of
inflammation on alloimmunization. We hypothesize that alloimmunization in individuals with SCD that occur in
the setting of acute inflammation differs mechanistically from that of alloimmunization that occurs in the setting
of chronic transfusion or in healthy individuals. We will compare the transcriptomes obtained in aim 2 to
scRNAseq data obtained from stored PBMCs from a cohort of 40 non-SCD individuals who developed
alloantibodies when challenged by Rh mismatched RBCs. We predict our analysis will allow us to identify
individuals at risk for alloimmunization before it occurs, and elucidate the role of inflammation in
alloimmunization, both in patients with SCD and in healthy individuals.

## Key facts

- **NIH application ID:** 11070287
- **Project number:** 5P01HL169552-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Vivien Andrea Sheehan
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $458,329
- **Award type:** 5
- **Project period:** 2023-09-10 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11070287

## Citation

> US National Institutes of Health, RePORTER application 11070287, Basic and Translational Mechanisms of Alloimmunization to RBC Transfusion.  Project 4 (5P01HL169552-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11070287. Licensed CC0.

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