# Responsiveness and non-responsiveness to transfused RBCs in mice and humans.

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $418,750

## Abstract

Background: It remains unclear why certain transfusion recipients make clinically significant RBC alloantibody
after antibody (“responders”), yet others are transfused hundreds of times without generating any detectable
alloantibodies (“non-responders”). We have discovered that the recipient inflammatory status at the time of
RBC transfusion, in combination with the ability of the recipients to sense type 1 interferons (IFN), are critical in
determining responder/non-responder status in our reductionist murine models. Further, recent studies in
humans suggest that the inflammation/alloimmunization connection transcends mice, though genetic variables
must also be considered.
Central Hypothesis: We hypothesize that inflammation (specifically type 1 IFN induction and sensing) and
genetic factors together determine which transfusion recipients will form alloantibodies following RBC
transfusion, with non-responders possibly being tolerant and not simply ignorant of RBC antigens. The
proposed studies utilize reductionist murine models, with blood donors expressing the authentic human blood
group antigens glycophorin A (hGPA) or KEL glycoprotein, and with genetically identical recipients generating
RBC alloantibodies only when transfusion occurs in the presence of an adjuvant or an ability to sense IFNs. In
depth in vivo studies of early immune activation events in responder and non-responder mice, in combination
with ex vivo studies of CD4+ T-cell subset phenotype, function, and transcriptome in responder and non-
responder humans, seek to increase knowledge of RBC alloimmunization.
Specific Aim 1: To investigate which recipient cell population(s) in mice mediate responsiveness to
transfused RBCs.
Specific Aim 2: To investigate the mechanism(s) through which non-responsiveness in mice occurs
following transfusion.
Specific Aim 3: To investigate differences in CD4+ T-cells in responder and non-responder humans.

## Key facts

- **NIH application ID:** 9918440
- **Project number:** 5R01HL132951-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** PATRICK G GALLAGHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918440

## Citation

> US National Institutes of Health, RePORTER application 9918440, Responsiveness and non-responsiveness to transfused RBCs in mice and humans. (5R01HL132951-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9918440. Licensed CC0.

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