# Alloimmunization and Humoral Response to Hemolysis

> **NIH NIH P01** · NEW YORK BLOOD CENTER · 2021 · $647,795

## Abstract

Abstract
Blood transfusions remain an important treatment modality for patients with sickle cell disease (SCD) and
thalassemia (Thal). However, 15-50% of these patients develop alloantibodies causing complications ranging
from difficulty in finding matched units to potentially life-threatening delayed hemolytic transfusion reactions
(DHTR). Increasing evidence suggest that free hemoglobin (Hb) and heme play central roles in many aspects
of the pathophysiology of hemolytic anemias, especially in SCD. With regards to alloimmunization, we have
previously identified weakened innate immunoregulatory function in response to free heme in alloimmunized
SCD patients with the implication that hemolysis is a potential alloimmunization risk factor. Our preliminary data
indicate that free heme can directly inhibit B plasma B cell differentiation in healthy donors and non-
alloimmunized but not alloimmunized SCD patients. Heme/hemolysis resulted in enhancement of T follicular
regulatory cell (TFR) suppressive activity, key in inhibiting B cell responses, in non-alloimmunized but not
alloimmunized SCD patients. We therefore posit that defective response to heme/hemolysis in B cells and TFR
cell increases their risk of alloimmunization. We hypothesize that heme-sensing pathways in key humoral
immune cells are critical in the regulation of SCD RBC alloimmunization. We will test our hypothesis by examining
key DOCK8/HO-1/ROS heme molecular pathways at basal level and during RBC transfusion in B cells (Aim1)
and TFR cells (Aim2) in patients with SCD. Using both in vitro and in vivo models, we will also test the efficacy of
drugs that target these pathways to switch off humoral immune response against transfused RBCs under
hemolytic conditions. We believe that elucidation of molecular pathways associated with the defective heme
response in humoral immune cells in alloimmunized patients is likely to lead to identification of potential
biomarkers of alloimmunization and DHTR in hemolytic disorders and novel therapeutic targets that can prevent
or even inhibit alloimmunization/DHTR.

## Key facts

- **NIH application ID:** 10220127
- **Project number:** 5P01HL149626-02
- **Recipient organization:** NEW YORK BLOOD CENTER
- **Principal Investigator:** Karina Yazdanbakhsh
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $647,795
- **Award type:** 5
- **Project period:** 2020-07-20 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220127

## Citation

> US National Institutes of Health, RePORTER application 10220127, Alloimmunization and Humoral Response to Hemolysis (5P01HL149626-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220127. Licensed CC0.

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