# Cyokine control of red blood cell alloimmunization

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $519,149

## Abstract

Summary. Red blood cell (RBC) alloimmunization remains a significant clinical problem in transfusion
medicine, particularly among those patients who require chronic transfusions. For those who are unfortunate
enough to generate multiple alloantibodies, provision of compatible antigen negative RBCs can be both time
and resource intensive. In rare cases, this can result in an inability to locate an otherwise life-saving therapy.
RBC alloantibodies are also responsible for hemolytic transfusion reactions (HTRs), causing substantial
morbidity and occasional mortality. HTRs result from two important immunological phenomena. The first is
the uniquely evanescent nature of RBC antibodies, whose rapid disappearance leads to false negative
screens in alloimmunized patients. The second is the recall antibody response elicited by re-exposure to
antigen via subsequent transfusion, where the rapid and robust increase in circulating antibodies drive HTRs.
Despite the significant clinical consequences of these phenomena, our understanding of the fundamental
molecular and cellular mechanisms regulating anti-RBC antibody generation, maintenance and recall is
remarkably limited. Accordingly, there are no effective therapeutic interventions available to alloimmunized
patients other than antigen avoidance. Our previous work has identified IL-6 as a key cytokine signal that
regulates both the initial alloimmunization response to RBCs as well as early T follicular helper cell (TFH)
differentiation. We are now interested in extending our findings to investigate the role of IL-6 signals in
controlling RBC alloantibody evanescence and recall responses. Given the pleomorphic nature of IL-6
signaling, we are interested in determining both the cellular targets (B vs. T cell), downstream signaling
molecules (STAT3), and cellular consequences (short-lived plasma cell, long-lived plasma cell, memory B cell
and memory TFH cell differentiation) regulated by IL-6 and required for RBC alloimmunization. Accordingly,
we will employ cutting-edge conditional genetic mouse mutants of IL-6R, STAT3, and BCL6 to directly
compare antibody and cellular responses to two different mouse models of RBC alloimmunization as well as
standard vaccination approaches. In so doing, we will better understand how the fundamental cellular and
molecular immune regulators of RBC alloimmunization vary for different RBC antigen systems, and also how
they compare to traditional immune stimulation. Furthermore, we will develop a pre-clinical mouse model
system to determine the therapeutic efficacy of targeting the IL-6/IL-6R signaling pathway for the prevention
and/or treatment of RBC alloimmunization, serving as key data for the subsequent consideration of IL-6R
antibody blocking therapies (such as Tocilizumab) in select, high-risk alloimmunized patients.

## Key facts

- **NIH application ID:** 9838808
- **Project number:** 5R01HL134691-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** CHANCE MARION JOHN LUCKEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $519,149
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838808

## Citation

> US National Institutes of Health, RePORTER application 9838808, Cyokine control of red blood cell alloimmunization (5R01HL134691-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838808. Licensed CC0.

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