# Immune Pathophysiology of Sickle Cell Disease

> **NIH NIH R35** · NEW YORK BLOOD CENTER · 2022 · $846,806

## Abstract

Project Abstract
A chronic inflammatory state is now considered a hallmark of sickle cell disease (SCD) resulting from ongoing
hemolytic insult to the underlying vasculature and repeated cycles of vaso-occlusion crisis (VOC). Transfusions
remain a cornerstone treatment for patients with SCD, but unlike other transfused patient populations, a higher
proportion (20-50%) of patients with SCD develop alloantibodies with potentially life-threatening sequalae. These
include poorly understood delayed transfusion reactions (DHTRs) whose occurrence, as well as clinical
progression from mild to severe, is unpredictable. A long-standing interest of our research program has been to
understand the underling immune mechanisms leading to SCD complications including VOC and transfusion
complications. Our studies have uncovered an underappreciate role of circulating monocytes and the innate
immune response to hemolysis, a hallmark of SCD, in transfusion complications including alloimmunization and
DHTRs. Our projected studies as part of this R35 will be focused on innate immune cellular pathways that
magnify the inflammatory SCD state versus the cells' heme protective pathways such as the heme detoxifying
key enzyme heme oxygenase 1 in alloimmunization and in the development of DHTRs. Our laboratory has also
identified a novel function for a subset of circulating monocytes, referred to as patrolling monocytes (PMo), in
their ability to scavenge and remove damaged endothelium and endothelial-attached sickle RBCs. The discovery
of a novel mechanism of action of PMo in SCD offers a paradigm shift in our understanding of VOC and opens
up the possibility that PMos can be manipulated to prevent painful VOC. An objective of the proposed studies in
this R35 is to understand the mechanisms by which PMo protect SCD vasculature and how they are affected
both functionally and numerically during a vaso-occlusive event with the goal to help establish their role in VOC
pathophysiology, and their potential as a therapeutic target for VOC. As we have done in the past, all the
proposed studies for both objectives will combine the use of in vivo mouse models, in vitro human model
systems, and patient samples to mechanistically dissect in a rigorous manner how specific immune cell types
and molecular pathways contribute to SCD alloimmunization and VOC. Altogether, we believe that our
laboratory's approach of integrating studies in humans and experimental models to mechanistically dissect
immune pathways that regulate SCD complications is likely to be impactful and generate novel findings in areas
critical to the NHLBI scientific mission.

## Key facts

- **NIH application ID:** 10353672
- **Project number:** 1R35HL161239-01
- **Recipient organization:** NEW YORK BLOOD CENTER
- **Principal Investigator:** Karina Yazdanbakhsh
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $846,806
- **Award type:** 1
- **Project period:** 2022-03-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353672

## Citation

> US National Institutes of Health, RePORTER application 10353672, Immune Pathophysiology of Sickle Cell Disease (1R35HL161239-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10353672. Licensed CC0.

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