Reticulocyte-mediated regulation of B cell activation and alloantibody formation

Active Project Grant Awarded Last action

Award ID
F32HL186724
Recipient
Awarding agency
Obligated
$80,266

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 0% complete
Place of performance
New York, NY 10032, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
A severe, and sometimes fatal, complication following red blood cell (RBC) transfusions is production of alloantibodies. Yet, despite the antigenic complexity of rbcs, the formation of alloantibodies is a rare and sporadic event. The unpredictable, selective nature of these alloantibody responses highlights a knowledge GAP in the understanding of how the immune system recognizes and responds to transfused rbcs. Recent findings reveal that the context in which RBC antigens are delivered, specifically the cellular composition of the transfused blood, profoundly influences the generation of antigen-specific alloantibodies and their persistence. Recent studies have revealed an unexpected role for reticulocytes (i.e., immature, metabolically active rbcs), in eliciting alloantibody formation following transfusion. Reticulocyte-rich RBC units, which are increasingly prevalent due to the overreliance on repeat volunteer blood donors for the US blood supply, have been shown to amplify and prolong anti-RBC alloantibody responses, even when all other donor, recipient, and antigen factors are matched. Additional novel findings reveal that reticulocytes are ingested by B cells, which are the sole producers of antibodies, and initiate pro-inflammatory signaling. Collectively, these observations challenge traditional perspectives on alloantibody generation that focus solely on antigenicity, and instead suggest that reticulocytes contribute distinct molecular cues during transfusion that modulate B cell responses. Therefore, this research tests the central hypothesis that transfused reticulocytes uniquely prime B cells, promoting context-dependent alloantibody production and durable immune memory. This work will define how transfused reticulocytes alter B cell fate and function by: (1) identifying the B cell populations and tissue sites engaged by reticulocytes, (2) determining the cellular and molecular pathways driving reticulocyte-mediated B cell activation and antibody production, and (3) elucidating the immunogenic properties of reticulocytes that distinguish them from mature rbcs. The studies employ innovative approaches, integrating in vivo transfusion and imaging, metabolic and transcriptional profiling, and spatial mapping. Insights gained from the proposed studies have the potential to resolve longstanding questions about why certain transfusions elicit alloimmune responses and why persistence of alloantibodies in recipients varies, advancing the basic understanding of humoral immunity and will inform transfusing medicine practice, such as identifying immunogenic donor units and improving transfusion safety. These findings will also deepen the fundamental understanding of how cellular context shapes immune responses, with broad potential applications across numerous therapeutic areas, including autoimmunity and transplantation. As a training fellowship, this work will provide rigorous interdisciplinary training in immunology and transfusion medicine within columbia university's collaborative, resource-rich research environment.

Quick answers

Who received award F32HL186724?

F32HL186724 was awarded to The Trustees Of Columbia University In The City Of New York by National Heart Lung and Blood Institute (National Institutes of Health) on December 15, 2026.

How much is award F32HL186724 worth?

$80,266 has been obligated on F32HL186724.

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