# Examination of Initiating Factors that Regulate Red Blood Cell Alloimmunization

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $125,247

## Abstract

Project Summary
Although Landsteiner's discovery of ABO(H) blood group antigens over a century ago allowed predictions of
red blood cell (RBC) compatibility prior to transfusion, in the 1930s several studies demonstrated that RBC
transfusion itself can also induce additional RBC alloantibodies capable of causing incompatible transfusion
reactions. RBC-induced alloantibodies against a variety of distinct RBC alloantigens can become particularly
problematic in individuals who require repeat transfusions, often making it difficult, if not impossible, to find
compatible RBCs. As a result, RBC alloantibody formation can significantly increase the mortality and
morbidity of patients who require chronic transfusions. However, no current strategies exist to actively inhibit
RBC-induced alloantibody formation following RBC transfusion therapy. This in part reflects a lack of
understanding regarding key initiating factors that regulate RBC-induced alloantibody formation. In order to
develop strategies with the potential to inhibit RBC-induced alloantibody formation, we used recently
developed mouse models of RBC alloimmunization to define key initiating events required for the production of
RBC alloantibodies following exposure to two disparate RBC alloantigens. Our preliminary results
demonstrate that removal of marginal zone (MZ) B cells or macrophages within the MZ prevents alloantibody
formation following exposure to two distinct RBC alloantigens. However, these unique RBC alloantigens
appear to differentially induce MZ constituents to engage type 1 interferon (INFαβ) or toll-like receptor
pathways. Furthermore, our preliminary data demonstrate that RBC alloantigens also possess the capacity to
induce CD4+ T cell-independent or CD4+ T cell-dependent antibody formation following RBC transfusion. As
previous studies suggest that marginal zone macrophages (MZM) and MZ B cells can work in a coordinated
fashion to induce CD4+ T cell-independent or CD4+ T cell-dependent immune responses, these results suggest
a critical link between MZM and MZ B cells in the generation of anti-RBC alloantibodies through both CD4+ T
cell-independent and CD4+ T cell-dependent processes, depending on the type of RBC alloantigen presented.
As a result, we hypothesize that MZ constituents play a central role in the initiation and orchestration of
immune responses induced by RBC transfusion. To test this hypothesis, we propose the following specific
aims: 1) Define the role of MZ B cells and MZM in IFNαβ-induced T cell-independent RBC alloantibody
formation. 2) Define the role of MZM and MZ B cells in CD4+ T cell-dependent RBC alloantibody
formation. We believe each of these aims provides a unique opportunity to identify common initiating factors
key to the immune response to distinct RBC alloantigens. In doing so, these studies will provide valuable
insight into potential targets for therapeutic mitigation of alloimmune responses to multiple RBC antigens in
patients who require c...

## Key facts

- **NIH application ID:** 10218737
- **Project number:** 7R01HL135575-05
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Sean R Stowell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $125,247
- **Award type:** 7
- **Project period:** 2020-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218737

## Citation

> US National Institutes of Health, RePORTER application 10218737, Examination of Initiating Factors that Regulate Red Blood Cell Alloimmunization (7R01HL135575-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10218737. Licensed CC0.

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